Alkylated cyclodextrin compositions and processes for preparing and using the same

ABSTRACT

The present disclosure is related to processes for efficient large-scale preparation of alkylated cyclodextrins. The processes of the present disclosure provide high purity alkylated cyclodextrins with high purity and low levels of chloride while improving efficiency, increasing batch size, and reducing total process time.

BACKGROUND Field

The present disclosure relates to processes for efficient, large-scalepreparation of high purity alkylated cyclodextrins, compositionscomprising alkylated cyclodextrins, and methods of using the same.

Description of the Related Art

Hydrophobic, hydrophilic, polymerized, ionized, non-ionized and manyother derivatives of cyclodextrins have been developed, and their use invarious industries has been established. Generally, cyclodextrinderivatization proceeds via reactions in which —OH groups at the 2-, 3-,and/or 6-position of the amylose rings of a cyclodextrin are replacedwith substituent groups. Substituents include neutral, anionic and/orcationic functional groups.

Known cyclodextrin derivatives such as alkylated cyclodextrins include,but are not limited to, sulfoalkyl ether cyclodextrins, alkyl ethercyclodextrins (e.g., methyl, ethyl and propyl ether cyclodextrins),hydroxyalkyl cyclodextrins, thioalkyl ether cyclodextrins, carboxylatedcyclodextrins (e.g., succinyl-β-cyclodextrin, and the like), sulfatedcyclodextrins, and the like. Alkylated cyclodextrins having more thanone type of functional group are also known, such as sulfoalkylether-alkyl ether-cyclodextrins (see, e.g., WO 2005/042584 and US2009/0012042, each of which is hereby incorporated by reference in itsentirety). In particular, alkylated cyclodextrins having 2-hydroxypropylgroups and/or sulfoalkyl ether groups have found use in pharmaceuticalformulations.

A sulfobutyl ether derivative of β-cyclodextrin (“SBE-β-CD”) has beencommercialized by CyDex Pharmaceuticals, Inc. as CAPTISOL®. The anionicsulfobutyl ether substituent improves the aqueous solubility and safetyof the parent β-cyclodextrin, which can reversibly form complexes withactive pharmaceutical agents, thereby increasing the solubility ofactive pharmaceutical agents and, in some cases, increase the stabilityof active pharmaceutical agents in aqueous solution. CAPTISOL® has achemical structure according to Formula X:

where R is —H or —(CH₂)₄—SO₃ ⁻Na⁺, and the average degree ofsubstitution with —(CH₂)₄—SO₃ ⁻Na⁺ is from 6 to 7.1.

Sulfoalkyl ether derivatized cyclodextrins (such as CAPTISOL®) areprepared using batch methods as described in, e.g., U.S. Pat. Nos.5,134,127, 5,376,645 and 6,153,746, each of which is hereby incorporatedby reference in its entirety.

Sulfoalkyl ether cyclodextrins and other derivatized cyclodextrins canalso be prepared according to the methods described in the followingpatents and published patent applications: U.S. Pat. Nos. 3,426,011;3,453,257; 3,453,259; 3,459,731; 4,638,058; 4,727,064; 5,019,562;5,173,481; 5,183,809; 5,241,059; 5,536,826; 5,594,125; 5,658,894;5,710,268; 5,756,484; 5,760,015; 5,846,954; 6,407,079; 7,625,878;7,629,331; 7,635,773; US2009/0012042; JP 05001102; and WO 01/40316; aswell as in the following non-patent publications: Lammers et al., Recl.Trav. Chim. Pays-Bas 91:733 (1972); Staerke 23:167 (1971); Adam et al.,J. Med. Chem. 45:1806 (2002); Qu et al., J. Inclusion Phenom.Macrocyclic Chem. 43:213 (2002); Tarver et al., Bioorg. Med. Chem.10:1819 (2002); Fromming et al., Cyclodextrins in Pharmacy (KluwerAcademic Publishing, Dordrecht, 1994); Modified Cyclodextrins: Scaffoldsand Templates for Supramolecular Chemistry (C. J. Easton et al. eds.,Imperial College Press, London, U K, 1999); New Trends in Cyclodextrinsand Derivatives (Dominique Duchene ed., Editions de Santé, Paris, F R,1991); Comprehensive Supramolecular Chemistry 3 (Elsevier Science Inc.,Tarrytown, NY); the entire disclosures of which are hereby incorporatedby reference.

Impurities present in an alkylated cyclodextrin composition can reducethe shelf-life and potency of an active agent composition. Impuritiescan be removed from an alkylated cyclodextrin composition by exposure to(e.g., mixing with) activated carbon. Methods for increasing the purityof alkylated cyclodextrins are described in U.S. Pat. Nos. 7,635,773,9,493,582, and 10,040,872, the disclosure of each of which are herebyincorporated by reference in its entirety.

As the use of alkylated cyclodextrins in pharmaceutical applicationsgrows in importance, a need exists for efficient, large-scale processesfor making alkylated cyclodextrins with suitable purity forpharmaceutical use.

SUMMARY

The present disclosure provides a process for preparing an alkylatedcyclodextrin composition, the process comprising: (a) mixing acyclodextrin with an alkylating agent to form a reaction milieucomprising an alkylated cyclodextrin; (b) conducting a first one or moreseparations to form a first solution comprising the alkylatedcyclodextrin, wherein the one of more separations comprisesdiafiltration through an ultrafiltration membrane; (c) treating thefirst solution with an activated carbon to produce a second alkylatedcyclodextrin solution; and (d) conducting a second one or moreseparations to form a third alkylated cyclodextrin solution, wherein theone or more separations comprises nanofiltration through ananofiltration membrane.

In some embodiments, solvent may be added to dilute the reaction milieuformed in step (a) prior to conducting the first one or moreseparations. In some specific embodiments, the solvent is water. In someembodiments, the concentration of the alkylated cyclodextrin in step (b)is less than 10% (w/w) prior to the first one or more separations. Insome embodiments, the concentration of the alkylated cyclodextrin instep (b) is less than 8% (w/w) prior to the first one or moreseparations. In some embodiments, the concentration of the alkylatedcyclodextrin in step (b) is less than 6% (w/w) prior to the first one ormore separations. In some embodiments, the concentration of thealkylated cyclodextrin in step (b) is from about 3% (w/w) to about 8%(w/w) or from about 4% (w/w) to about 6% (w/w) prior to the first one ormore separations.

In some embodiments, the ultrafiltration membrane in step (b) has amolecular weight cut-off (MWCO) of about 1000 Da or lower. In someembodiments, the ultrafiltration membrane in step (b) has a MWCO ofabout 1000 Da. In other embodiments, the ultrafiltration membrane instep (b) has a MWCO of about 650 Da. In yet other embodiments, theultrafiltration membrane in step (b) has a MWCO of about 500 Da. In someembodiments, the ultrafiltration membrane in step (b) has a MWCO ofabout 500 to about 1000 Da.

In some embodiments, the activated carbon may be prepared by a methodcomprising the step of subjecting the activated carbon to an initialcarbon washing process comprising adding a portion of the first solutioncomprising the alkylated cyclodextrin from step (b) to the carbon,soaking the carbon in the first solution, and eluting and discarding thesolution.

In some embodiments, the activated carbon may be further subjected to awashing process comprising flowing water over the carbon after theinitial carbon washing process and eluting the water. In someembodiments, the water is flowed over the carbon for at least 30minutes. In other embodiments, the water is flowed over the carbon forat least two hours. In some embodiments, the eluted wash water has aresidual conductivity of 10 pS/cm or less

In some embodiments, the activated carbon is phosphate free. In someembodiments, the activated carbon is steam activated. In otherembodiments, the activated carbon is acid activated with, e.g.,phosphoric acid. In yet other embodiments, the activated carbon isactivated with zinc chloride. In some embodiments, the activated carbonis granular.

In some embodiments, the concentration of the alkylated cyclodextrin inthe second alkylated cyclodextrin solution introduced into step (d) isfrom about 3% (w/w) to about 8% (w/w). In some embodiments, theconcentration of the alkylated cyclodextrin in the second alkylatedcyclodextrin solution introduced into step (d) is from about 4% (w/w) toabout 7% (w/w). In some embodiments, the concentration of the alkylatedcyclodextrin in the second alkylated cyclodextrin solution introducedinto step (d) is about 5% (w/w).

In some embodiments, the nanofiltration membrane in step (d) has a MWCOof about 500 Da or lower. In some embodiments, wherein thenanofiltration membrane has a MWCO of about 500 Da. In otherembodiments, the nanofiltration membrane has a MWCO of about 400 Da. Insome embodiments, the nanofiltration membrane has a MWCO of about 300Da. In some embodiments, the nanofiltration membrane has a MWCO of about200 Da. In some embodiments, the nanofiltration membrane has a MWCO ofabout 150 Da. In some embodiments, the nanofiltration membrane has aMWCO of about 150-500 Da. In some embodiments, the nanofiltrationmembrane has a MWCO of about 300-500 Da.

In some embodiments, the nanofiltration is conducted for a period of 30minutes to 12 hours. In some embodiments, the nanofiltration isconducted for a period of about 1 hour to about 3 hours. In someembodiments, the nanofiltration is conducted for a period of 2 hours. Insome embodiments, the nanofiltration is conducted for a period of 3hours.

In some embodiments, the concentration of the alkylated cyclodextrin inthe third alkylated cyclodextrin solution is from about 10% (w/w) toabout 25% (w/w). In some embodiments, the concentration of the alkylatedcyclodextrin in the third alkylated cyclodextrin solution is from about15% (w/w) to about 20% (w/w). In some embodiments, the concentration ofthe alkylated cyclodextrin in the third alkylated cyclodextrin solutionis about 18% (w/w) to about 20% (w/w).

In some embodiments, the third alkylated cyclodextrin solution (i.e.,the solution formed after conducting a second one or more separations,wherein the one or more separations comprises nanofiltration through ananofiltration membrane) may be concentrated for a period of about 2hours to about 24 hours to form a fourth alkylated cyclodextrinsolution. In some embodiments, the third alkylated cyclodextrin solutionmay be concentrated for a period of about 6 hours to about 18 hours toform a fourth alkylated cyclodextrin solution. In some embodiments, thethird alkylated cyclodextrin solution may be concentrated for a periodof about 8 hours to about 12 hours to form a fourth alkylatedcyclodextrin solution. In some embodiments, the third alkylatedcyclodextrin solution may be concentrated for a period of about 9 hoursto form a fourth alkylated cyclodextrin solution. In some embodiments,concentrating the third alkylated cyclodextrin solution is performed bydistillation.

In some embodiments, the concentration of the alkylated cyclodextrin inthe fourth alkylated cyclodextrin solution is from about 30% (w/w) toabout 70% (w/w). In some embodiments, the concentration of the alkylatedcyclodextrin in the fourth alkylated cyclodextrin solution is from about40% (w/w) to about 60% (w/w). In some embodiments, the concentration ofthe alkylated cyclodextrin in the fourth alkylated cyclodextrin solutionis about 50% (w/w).

In some embodiments, the process disclosed herein further comprisingremoving some or all of the solvent from the fourth alkylatedcyclodextrin solution to form a solid alkylated cyclodextrin. In someembodiments, solvent is removed by distillation, lyophilization, orspray-drying.

In some embodiments, the solid alkylated cyclodextrin formed by theprocesses described herein comprises less than 500 ppm of a phosphate.In some embodiments, the solid alkylated cyclodextrin comprises lessthan 125 ppm of a phosphate. In some embodiments, the solid alkylatedcyclodextrin comprises less than 0.05% (w/w) of a chloride. In someembodiments, the solid alkylated cyclodextrin comprises less than 0.01%(w/w) of a chloride. In some embodiments, the solid alkylatedcyclodextrin comprises less than 0.002% (w/w) of a chloride.

In some embodiments, the processes described herein comprise preparing asingle batch of alkylated cyclodextrin wherein the starting cyclodextrinhas a mass greater than 275 kg. In other embodiments, the processesdescribed herein comprise preparing a single batch of alkylatedcyclodextrin wherein the starting cyclodextrin has a mass greater than300 kg. In yet other embodiments, the processes described hereincomprise preparing a single batch of alkylated cyclodextrin wherein thestarting cyclodextrin has a mass greater than 350 kg.

In some embodiments, the alkylated cyclodextrin has an average degree ofsubstitution of 2 to 9. In some embodiments the alkylated cyclodextrinhas an average degree of substitution of 4.5 to 7.5. In someembodiments, the alkylated cyclodextrin has an average degree ofsubstitution of 6 to 7.5.

In some embodiments, the alkylated cyclodextrin prepared by theprocesses disclosed herein is a sulfoalkyl ether cyclodextrin of Formula(II):

wherein p is 4, 5, or 6, and R₁ is independently selected at eachoccurrence from —OH or —O—(C₂-C₆ alkylene)-SO₃ ⁻-T, wherein T isindependently selected at each occurrence from pharmaceuticallyacceptable cations, provided that at least one R₁ is —OH and at leastone R₁ is O—(C₂-C₆ alkylene)-SO₃ ⁻-T.

In some embodiments, R₁ is independently selected at each occurrencefrom —OH or —O—(C₄ alkylene)-SO₃ ⁻-T, and -T is Na⁺ at each occurrence.

In some embodiments, the processes described herein may further comprisecombining the solid alkylated cyclodextrin with one or more excipients.In some embodiments, the processes described herein may further comprisecombining the solid alkylated cyclodextrin with an active agent.

Further embodiments, features, and advantages of the present disclosure,as well as the composition, structure, and operation of variousembodiments of the present disclosure, are described in detail belowwith reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic representation of a purification process forthe alkylated cyclodextrin preparation described herein.

DETAILED DESCRIPTION

As used herein, percentages refer to “% by weight” and/or “w/w” (weightby weight concentration) unless otherwise indicated.

References to spatial descriptions (e.g., “above,” “below,” “up,”“down,” “top,” “bottom,” etc.) made herein are for purposes ofdescription and illustration only, and should be interpreted asnon-limiting upon the processes, equipment, compositions and products ofany method of the present disclosure, which can be spatially arranged inany orientation or manner.

Alkylated Cyclodextrin

An “alkylated cyclodextrin composition” is a composition comprisingalkylated cyclodextrins having a degree of substitution or an averagedegree of substitution (ADS) for a specified substituent. An alkylatedcyclodextrin composition comprises a distribution of alkylatedcyclodextrin species differing in the individual degree of substitutionspecified substituent for each species, wherein the specifiedsubstituent for each species is the same. As used herein, an “alkylatedcyclodextrin composition” is composition which does not contain separateor second substance as a pharmaceutically active agent). For example, acyclodextrin composition may comprise at least 90% (w/w) cyclodextrin,at least 95% (w/w) cyclodextrin, at least 97% (w/w) cyclodextrin, atleast 99% (w/w) cyclodextrin, at least 99.9% (w/w) cyclodextrin, or atleast 99.99% (w/w) cyclodextrin.

The alkylated cyclodextrin can be a water soluble alkylatedcyclodextrin, which is any alkylated cyclodextrin exhibiting enhancedwater solubility over its corresponding underivatized parentcyclodextrin and having a molecular structure based upon α-, β- orγ-cyclodextrin. In some embodiments, a derivatized cyclodextrin preparedby a process of the present disclosure has a solubility in water of 100mg/mL or higher, or a solubility in water of less than 100 mg/mL.

The cyclodextrin can be derivatized with neutral, anionic or cationicsubstituents at the C2, C3, or C6 positions of the individualsaccharides forming the cyclodextrin ring. Suitable water solublealkylated cyclodextrins are described herein. The alkylated cyclodextrincan also be a water insoluble alkylated cyclodextrin or a alkylatedcyclodextrin possessing a lower water solubility than its correspondingunderivatized parent cyclodextrin.

As used herein, a “substituent precursor” or “alkylating agent” refersto a compound, reagent, moiety, or substance capable of reacting with an—OH group present on a cyclodextrin. In some embodiments, thederivatized cyclodextrin includes a substituent such as a sulfoalkylether group, an ether group, an alkyl ether group, an alkenyl ethergroup, a hydroxyalkyl ether group, a hydroxyalkenyl ether group, athioalkyl ether group, an aminoalkyl ether group, a mercapto group, anamino group, an alkylamino group, a carboxyl group, an ester group, anitro group, a halo group, an aldehyde group, a 2,3-epoxypropyl group,and combinations thereof. In some embodiments, alkylating agents includean alkyl sultone (e.g., 1,4-butane sultone, 1,5-pentane sultone,1,3-propane sultone, and the like). An alkylated cyclodextrin is acyclodextrin in which one or more —OH groups is replaced with an —O—Rgroup, wherein the R contains an alkyl moiety. For example, the —O—Rgroup can be an alkyl ether or a sulfoalkyl ether.

After reaction, purification, and/or isolation, the alkylatedcyclodextrin of the present disclosure can comprise small amounts (e.g.,1% or less, 0.5% or less, 0.1% or less, 0.05% or less, 0.001% or less,0.0005% or less, or 0.0001% or less, by weight) of a cyclodextrinstarting material (e.g., an underivatized parent cyclodextrin).

The alkylated cyclodextrin can be present in high purity form. See U.S.Pat. Nos. 7,635,773; 9,493,582; and 10,040,872, the disclosure of eachof which are hereby incorporated by reference in its entirety. In someembodiments, the alkylated cyclodextrin is a high purity SAE-CDcomposition having a reduced amount of drug-degrading agent. Thealkylated cyclodextrin optionally has a reduced amount of phosphate orexcludes phosphate entirely. The alkylated cyclodextrin also optionallyhas low amounts of a color-forming agent. The SAE-CD can also havereduced amounts of 1,4-butane sultone and 4-hydroxy-butane-1-sulfonicacid. The SAE-CD can also have reduced amounts of chloride.

An alkylated cyclodextrin of the present disclosure provides unexpectedadvantages over other structurally related alkylated cyclodextrins. By“structurally related” is meant, for example, that the substituent ofthe alkylated cyclodextrin in the composition is essentially the same asthe substituent of the other alkylated cyclodextrin to which it is beingcompared. Exemplary advantages can include an enhanced purity, reducedcontent of pyrogens, reduced content of drug-degrading components,reduced content of color-forming agents, reduced content of unreactedsubstituent precursor, and/or reduced content of unreacted cyclodextrinstarting material. An exemplary advantage also includes a reducedchloride content and/or a reduced phosphate content.

A water soluble alkylated cyclodextrin composition can comprise asulfoalkyl ether cyclodextrin (SAE-CD) compound, or mixture ofcompounds, of the Formula I:

wherein: n is 4, 5 or 6; wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉are independently —H, a straight-chain or branched C₁-C₈-(alkylene)-SO₃⁻ group, or an optionally substituted straight-chain or branched C₁-C₆group; wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ isa straight-chain or branched C₁-C₈-(alkylene)-SO₃ ⁻ group.

In some embodiments, the SAE-CD is a water-soluble alkylatedcyclodextrin of Formula II:

wherein: p is 4, 5 or 6;

-   -   R₁ is independently selected at each occurrence from —OH or        -SAE-T;    -   -SAE- is a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, wherein at least one        SAE is independently a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, a        —O—(CH₂)_(g)SO₃ ⁻ group, wherein g is 2 to 6, or 2 to 4, (e.g.        —OCH₂CH₂CH₂SO₃ ⁻ or —OCH₂CH₂CH₂CH₂SO₃ ⁻); and -T is        independently selected at each occurrence from the group        consisting of pharmaceutically acceptable cations, which group        includes, for example, H⁺, alkali metals (e.g., Li⁺, Na⁺, K⁺),        alkaline earth metals (e.g., Ca⁺², Mg⁺²), ammonium ions and        amine cations such as the cations of (C₁-C₆)-alkylamines,        piperidine, pyrazine, (C₁-C₆)-alkanolamine, ethylenediamine and        (C₄-C₈)-cycloalkanolamine among others; provided that at least        one R₁ is a hydroxyl moiety and at least one R₁ is -SAE-T.

In some embodiments, T may be associated with an ion exchange resin,poly-L-lysine, polycationic chitosan, or any combination thereof.

When at least one R₁ of a derivatized cyclodextrin molecule is -SAE-T,the degree of substitution, in terms of the -SAE-T moiety, is understoodto be at least one (1). When the term -SAE- is used to denote asulfoalkyl-(alkylsulfonic acid)-ether moiety it being understood thatthe -SAE- moiety comprises a cation (-T) unless otherwise specified.Accordingly, the terms “SAE” and “—SAE-T” can, as appropriate, be usedinterchangeably herein.

Since SAE-CD is a poly-anionic cyclodextrin, it can be provided indifferent salt forms. Suitable counterions include cationic organicatoms or molecules and cationic inorganic atoms or molecules. The SAE-CDcan include a single type of counterion or a mixture of differentcounterions. The properties of the SAE-CD can be modified by changingthe identity of the counterion present. For example, a first salt formof a SAE-CD composition can possess greater osmotic potential or greaterwater activity reducing power than a different second salt form of sameSAE-CD.

In some embodiments, a sulfoalkyl ether cyclodextrin is complexed withone or more pharmaceutically acceptable cations selected from, e.g., H⁺,alkali metals (e.g., Li⁺, Na⁺, K⁺), alkaline earth metals (e.g., Ca⁺²,Mg⁺²), ammonium ions and amine cations such as the cations of(C₁-C₆)-alkylamines, piperidine, pyrazine, (C₁-C₆)-alkanolamine,ethylenediamine and (C₄-C₈)-cycloalkanolamine, and the like, andcombinations thereof.

Further exemplary sulfoalkyl ether (SAE)-CD derivatives include:

TABLE 1 SAE_(x)-α-CD SAE_(x)-β-CD SAE_(x)-γ-CD (Sulfoethylether)_(x)-α-CD (Sulfoethyl ether)_(x)-β-CD (Sulfoethyl ether)_(x)-γ-CD(Sulfopropyl ether)_(x)-α-CD (Sulfopropyl ether)_(x)-β-CD (Sulfopropylether)_(x)-γ-CD (Sulfobutyl ether)_(x)-α-CD (Sulfobutyl ether)_(x)-β-CD(Sulfobutyl ether)_(x)-γ-CD (Sulfopentyl ether)_(x)-α-CD (Sulfopentylether)_(x)-β-CD (Sulfopentyl ether)_(x)-γ-CD (Sulfohexyl ether)_(x)-α-CD(Sulfohexyl ether)_(x)-β-CD (Sulfohexyl ether)_(x)-γ-CDwherein x denotes the average degree of substitution. In someembodiments, the alkylated cyclodextrins are formed as salts.

Various embodiments of a sulfoalkyl ether cyclodextrin includeeicosa-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin,heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin,heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin,heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin,andheptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(sulfomethyl)-β-cyclodextrin.Other known alkylated cyclodextrins containing a sulfoalkyl moietyinclude sulfoalkylthio and sulfoalkylthioalkyl ether derivatives such asoctakis-(S-sulfopropyl)-octathio-7-cyclodextrin,octakis-O-[3-[(2-sulfoethyl)thio]propyl]-β-cyclodextrin], andoctakis-S-(2-sulfoethyl)-octathio-7-cyclodextrin.

In some embodiments, an alkylated cyclodextrin composition of thepresent disclosure is a sulfoalkyl ether-β-cyclodextrin compositionhaving an ADS of 2 to 9, 4 to 8, 4 to 7.5, 4 to 7, 4 to 6.5, 4.5 to 8,4.5 to 7.5, 4.5 to 7, 5 to 8, 5 to 7.5, 5 to 7, 5.5 to 8, 5.5 to 7.5,5.5 to 7, 5.5 to 6.5, 6 to 8, 6 to 7.5, 6 to 7.1, 6.5 to 7.1, 6.2 to6.9, or 6.5 per alkylated cyclodextrin, and the remaining substituentsare —H.

In some embodiments, the alkylated cyclodextrin is a compound of FormulaIII:

wherein n is 4, 5 or 6, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉are independently selected from: —H, a straight-chain or branchedC₁-C₈-(alkylene)-SO₃ ⁻ group, and an optionally substitutedstraight-chain or branched C1-C6 group.

A water soluble alkylated cyclodextrin composition can comprise an alkylether (AE)-cyclodextrin compound, or mixture of compounds, of theFormula IV:

wherein: m is 4, 5 or 6; R is independently selected at each occurrencefrom the group consisting of —OH and AE; and AE is —O—(C₁-C₆ alkyl);provided that at least one R is —OH; and at least one AE is present.

Further exemplary AE-CD derivatives include:

TABLE 2 (Alkylether)_(y)-α-CD (Alkylether)_(y)-β-CD(Alkylether)_(y)-γ-CD ME_(y)-α-CD ME_(y)-β-CD ME_(y)-γ-CD EE_(y)-α-CDEE_(y)-β-CD EE_(y)-γ-CD PE_(y)-α-CD PE_(y)-β-CD PE_(y)-γ-CD BE_(y)-α-CDBE_(y)-β-CD BE_(y)-γ-CD PtE_(y)-α-CD PtE_(y)-β-CD PtE_(y)-γ-CDHE_(y)-α-CD HE_(y)-β-CD HE_(y)-γ-CD

wherein ME denotes methyl ether, EE denotes ethyl ether, PE denotespropyl ether, BE denotes butyl ether, PtE denotes pentyl ethyl, HEdenotes hexyl ether, and y denotes the average degree of substitution.

A water soluble alkylated cyclodextrin composition can comprise aHAE-cyclodextrin compound, or mixture of compounds, of the Formula V:

wherein: “v” is 4, 5 or 6; “Q” is independently selected at eachoccurrence from the group consisting of —OH, and -HAE; and HAE isHO(C₁-C₆ alkyl)-O—, provided that at least one -HAE moiety is present.

Further exemplary hydroxyalkyl ether (HAE)-CD derivatives include:

TABLE 3 (HAE)_(z)-α-CD (HAE)_(z)-β-CD (HAE)_(z)-γ-CD HMEz-α-CD HMEz-β-CDHMEz-γ-CD HEEz-α-CD HEEz-β-CD HEEz-γ-CD HPEz-α-CD HPEz-β-CD HPEz-γ-CDHBEz-α-CD HBEz-β-CD HBEz-γ-CD HPtEz-α-CD HPtEz-β-CD HPtEz-γ-CD HHEz-α-CDHHEz-β-CD HHEz-γ-CD

wherein HME denotes hydroxymethyl ether, HEE denotes hydroxyethyl ether,HPE denotes hydroxypropyl ether, HBE denotes hydroxybutyl ether, HPtEdenotes hydroxypentyl ether, HHE denotes hydroxyhexyl ether, and zdenotes the average degree of substitution.

A water soluble alkylated cyclodextrin composition can comprise aSAE-AE-CD compound, or mixture of compounds, of Formula VI:

wherein: “v” is 4, 5 or 6; “A” is independently selected at eachoccurrence from the group consisting of —OH, -SAET and -AE; x is thedegree of substitution for the SAET moiety and is 1 to 3v+5; y is thedegree of substitution for the AE moiety and is 1 to 3v+5; -SAE is—O—(C₂-C₆ alkylene)-SO₃ ⁻; T is independently at each occurrence acation; and AE is —O(C₁-C₃ alkyl); provided that at least one -SAETmoiety and at least one -AE moiety are present; and the sum of x, y andthe total number of —OH groups in an alkylated cyclodextrin is 3v+6.

Specific embodiments of the derivatives of the present disclosureinclude those wherein: 1) the alkylene moiety of the SAE has the samenumber of carbons as the alkyl moiety of the AE; 2) the alkylene moietyof the SAE has a different number of carbons than the alkyl moiety ofthe AE; 3) the alkyl and alkylene moieties are independently selectedfrom the group consisting of a straight chain or branched moiety; 4) thealkyl and alkylene moieties are independently selected from the groupconsisting of a saturated or unsaturated moiety; 5) the ADS for the SAEgroup is greater than or approximates the ADS for the AE group; or 6)the ADS for the SAE group is less than the ADS for the AE group.

A water soluble alkylated cyclodextrin composition can comprise aSAE-HAE-CD compound, or mixture of compounds, of Formula VII:

wherein: “v” is 4, 5 or 6; “X” is independently selected at eachoccurrence from the group consisting of —OH, SAET and HAE; x is thedegree of substitution for the SAET moiety and is 1 to 3w+5; y is thedegree of substitution for the HAE moiety and is 1 to 3w+5; -SAE is—O—(C₂-C₆ alkylene)-SO₃ ⁻; T is independently at each occurrence acation; and HAE is HO—(C₁-C₆ alkyl)-O—; provided that at least one -SAETmoiety and at least one -HAE moiety are present; and the sum of x, y andthe total number of —OH groups in an alkylated cyclodextrin is 3w+6.

The alkylated cyclodextrin can include SAE-CD, HAE-CD, SAE-HAE-CD,HANE-CD, HAE-AE-CD, HAE-SAE-CD, AE-CD, SAE-AE-CD, neutral cyclodextrin,anionic cyclodextrin, cationic cyclodextrin, halo-derivatizedcyclodextrin, amino-derivatized cyclodextrin, nitrile-derivatizedcyclodextrin, aldehyde-derivatized cyclodextrin, carboxylate-derivatizedcyclodextrin, sulfate-derivatized cyclodextrin, sulfonate-derivatizedcyclodextrin, mercapto-derivatized cyclodextrin, alkylamino-derivatizedcyclodextrin, or succinyl-derivatized cyclodextrin.

In some embodiments, alkylated cyclodextrins such as mixed etheralkylated cyclodextrins include, by way of example, those listed Table 4below.

TABLE 4 Mixed ether CD derivative Mixed ether CD derivative Mixed etherCD derivative Sulfobutyl-hydroxybutyl-CD Sulfopropyl-hydroxybutyl-CDSulfoethyl-hydroxybutyl-CD (SBE-HBE-CD) (SPE-HBE-CD) (SEE-HBE-CD)Sulfobutyl-hydroxypropyl-CD Sulfopropyl-hydroxypropyl-CDSulfoethyl-hydroxypropyl-CD (SBE-HPE-CD) (SPE-HPE-CD) (SEE-HPE-CD)Sulfobutyl-hydroxyethyl-CD Sulfopropyl-hydroxyethyl-CDSulfoethyl-hydroxyethyl-CD (SBE-HEE-CD) (SPE-HEE-CD) (SEE-HEE-CD)Sulfobutyl-hydroxybutenyl-CD Sulfopropyl-hydroxybutenyl-CDSulfoethyl-hydroxybutenyl-CD (SBE-HBNE-CD) (SPE-HBNE-CD) (SEE-HBNE-CD)Sulfobutyl-ethyl Sulfopropyl-ethyl Sulfoethyl-ethyl (SBE-EE-CD)(SPE-EE-CD) (SEE-EE-CD) Sulfobutyl-methyl Sulfopropyl-methylSulfoethyl-methyl (SBE-ME-CD) (SPE-ME-CD) (SEE-ME-CD) Sulfobutyl-propylSulfopropyl-propyl Sulfoethyl-propyl (SBE-PE-CD) (SPE-PE-CD) (SEE-PE-CD)Sulfobutyl-butyl Sulfopropyl-butyl Sulfoethyl-butyl (SBE-BE-CD)(SPE-BE-CD) (SEE-BE-CD) Sulfobutyl-carboxymethyl-CDSulfopropyl-carboxymethyl-CD Sulfoethyl-carboxymethyl-CD (SBE-CME-CD)(SPE-CME-CD) (SEE-CME-CD) Sulfobutyl-carboxyethyl-CDSulfopropyl-carboxyethyl-CD Sulfoethyl-carboxyethyl-CD (SBE-CEE-CD)(SPE-CEE-CD) (SEE-CEE-CD) Sulfobutyl-acetate-CD Sulfopropyl-acetate-CDSulfoethyl-acetate-CD (SBE-AA-CD) (SPE-AA-CD) (SEE-AA-CD)Sulfobutyl-propionate-CD Sulfopropyl-propionate-CDSulfoethyl-propionate-CD (SBE-PA-CD) (SPE-PA-CD) (SEE-PA-CD)Sulfobutyl-butyrate-CD Sulfopropyl-butyrate-CD Sulfoethyl-butyrate-CD(SBE-BA-CD) (SPE-BA-CD) (SEE-BA-CD) Sulfobutyl- Sulfopropyl- Sulfoethyl-methoxycarbonyl-CD methoxycarbonyl-CD methoxycarbonyl-CD (SBE-MC-CD)(SPE-MC-CD) (SEE-MC-CD) Sulfobutyl- Sulfopropyl- Sulfoethyl-ethoxycarbonyl-CD ethoxycarbonyl-CD ethoxycarbonyl-CD (SBE-EC-CD)(SPE-EC-CD) (SEE-EC-CD) Sulfobutyl- Sulfopropyl- Sulfoethyl-propoxycarbonyl-CD propoxycarbonyl-CD propoxycarbonyl-CD (SBE-PC-CD)(SPE-PC-CD) (SEE-PC-CD) Hydroxybutyl- Hydroxypropyl- Hydroxyethyl-hydroxybutenyl-CD hydroxybutenyl-CD hydroxybutenyl-CD (HBE-HBNE-CD)(HPE-HBNE-CD) (HEE-HBNE-CD) Hydroxybutyl-ethyl-CD Hydroxypropyl-ethyl-CDHydroxyethyl-ethyl-CD (HBE-EE-CD) (HPE-EE-CD) (HEE-EE-CD)Hydroxybutyl-methyl-CD Hydroxypropyl-methyl-CD Hydroxyethyl-methyl-CD(HBE-ME-CD) (HPE-ME-CD) (HEE-ME-CD) Hydroxybutyl-propyl-CDHydroxypropyl-propyl-CD Hydroxyethyl-propyl-Cd (HBE-PE-CD) (HPE-PE-CD)(HEE-PE-CD) Hydroxybutyl-butyl Hydroxypropyl-butyl Hydroxyethyl-butyl(HBE-BE-CD) (HPE-BE-CD) (HEE-BE-CD) Hydroxybutyl- Hydroxypropyl-Hydroxyethyl- carboxymethyl-CD carboxymethyl-CD carboxymethyl-CD(HBE-CME-CD) (HPE-CME-CD) (HEE-CME-CD) Hydroxybutyl-carboxyethyl-CDHydroxypropyl-carboxyethyl-CD Hydroxyethyl-carboxyethyl-CD (HBE-CEE-CD)(HPE-CEE-CD) (HEE-CEE-CD) Hydroxybutyl-acetate-CDHydroxypropyl-acetate-CD Hydroxyethyl-acetate-CD (HBE-AA-CD) (HPE-AA-CD)(HEE-AA-CD) Hydroxybutyl-propionate-CD Hydroxypropyl-propionate-CDHydroxyethyl-propionate-CD (HBE-PA-CD) (HPE-PA-CD) (HEE-PA-CD)Hydroxybutyl-butyrate-CD Hydroxypropyl-butyrate-CDHydroxyethyl-butyrate-CD (HBE-BA-CD) (HPE-BA-CD) (HEE-BA-CD)Hydroxybutyl- Hydroxypropyl- Hydroxyethyl- methoxycarbonyl-CDmethoxycarbonyl-CD methoxycarbonyl-CD (HBE-MC-CD) (HPE-MC-CD)(HEE-MC-CD) Hydroxybutyl- Hydroxypropyl- Hydroxyethyl- ethoxycarbonyl-CDethoxycarbonyl-CD ethoxycarbonyl-CD (HBE-EC-CD) (HPE-EC-CD) (HEE-EC-CD)Hydroxybutyl- Hydroxypropyl- Hydroxyethyl- propoxycarbonyl-CDpropoxycarbonyl-CD propoxycarbonyl-CD (HBE-PC-CD) (HPE-PC-CD)(HEE-PC-CD) Hydroxybutenyl-ethyl-CD Hydroxypropenyl-ethyl-CDHydroxypentenyl-ethyl-CD (HBNE-EE-CD) (HPNE-EE-CD) (HPTNE-EE-CD)Hydroxybutenyl-methyl-CD Hydroxypropenyl-methyl-CDHydroxypentenyl-methyl-CD (HBNE-ME-CD) (HPNE-ME-CD) (HPTNE-ME-CD)Hydroxybutenyl-propyl-CD Hydroxypropenyl-propyl-CDHydroxypentenyl-propyl-CD (HBNE-PE-CD) (HPNE-PE-CD) (HPTNE-PE-CD)Hydroxybutenyl-butyl-CD Hydroxypropenyl-butyl-CDHydroxypentenyl-butyl-CD (HBNE-BE-CD) (HPNE-BE-CD) (HPTNE-BE-CD)Hydroxybutenyl- Hydroxypropenyl- Hydroxypentenyl- carboxymethyl-CDcarboxymethyl-CD carboxymethyl-CD (HBNE-CME-CD) (HPNE-CME-CD)(HPTNE-CME-CD) Hydroxybutenyl- Hydroxypropenyl- Hydroxypentenyl-carboxyethyl-CD carboxyethyl-CD carboxyethyl-CD (HBNE-CEE-CD)-(HPNE-CEE-CD) (HPTNE-CEE-CD) Hydroxybutenyl-acetate-CDHydroxypropenyl-acetate-CD Hydroxypentenyl-acetate-CD (HBNE-AA-CD)(HPNE-AA-CD) (HPTNE-AA-CD) Hydroxybutenyl- Hydroxypropenyl-Hydroxypentenyl- propionate-CD propionate-CD propionate-CD (HBNE-PA-CD)(HPNE-PA-CD) (HPTNE-PA-CD) Hydroxybutenyl-butyrate-CDHydroxypropenyl-butyrate-CD Hydroxypentenyl-butyrate-CD (HBNE-BA-CD)(HPNE-BA-CD) (HPTNE-BA-CD) Hydroxybutenyl- Hydroxypropenyl-Hydroxypentenyl- methoxycarbonyl-CD methoxycarbonyl-CDmethoxycarbonyl-CD (HBNE-MC-CD) (HPNE-MC-CD) (HPTNE-MC-CD)Hydroxybutenyl- Hydroxypropenyl- Hydroxypentenyl- ethoxycarbonyl-CDethoxycarbonyl-CD ethoxycarbonyl-CD (HBNE-EC-CD) (HPNE-EC-CD)(HPTNE-EC-CD) Hydroxybutenyl- Hydroxypropenyl- Hydroxypentenyl-propoxycarbonyl-CD propoxycarbonyl-CD propoxycarbonyl-CD (HBNE-PC-CD)(HPNE-PC-CD) (HPTNE-PC-CD)

Additional examples of alkylated cyclodextrins that may be prepared bythe methods disclosed herein are described in U.S. Pat. Nos. 5,438,133,6,479,467, and 6,610,671, the disclosure of each of which isincorporated by reference herein in its entirety.

Within a given alkylated cyclodextrin composition, the substituents ofthe alkylated cyclodextrin(s) thereof can be the same or different. Forexample, SAE or HAE moieties can have the same type or different type ofalkylene (alkyl) radical upon each occurrence in an alkylatedcyclodextrin composition. In such embodiments, the alkylene radical inthe SAE or HAE moiety can be ethyl, propyl, butyl, pentyl or hexyl ineach occurrence in an alkylated cyclodextrin composition.

The alkylated cyclodextrins can differ in their degree of substitutionby functional groups, the number of carbons in the functional groups,their molecular weight, the number of glucopyranose units contained inthe base cyclodextrin used to form the derivatized cyclodextrin and ortheir substitution patterns. In addition, the derivatization of acyclodextrin with functional groups occurs in a controlled, although notexact manner. For this reason, the degree of substitution is actually anumber representing the average number of functional groups percyclodextrin (for example, SBE₇-β-CD has an average of 7 substitutionsper cyclodextrin). Thus, it has an average degree of substitution(“ADS”) of 7. In some embodiments, the ADS may be determined bytechniques include capillary electrophoresis (CE), high performanceliquid chromatography (HPLC), nuclear magnetic resonance (NMR)spectroscopy, or a combination thereof. In addition, the regiochemistryof substitution of the hydroxyl groups of the cyclodextrin is variablewith regard to the substitution of specific hydroxyl groups of thehexose ring. For this reason, substitution of the different hydroxylgroups is likely to occur during manufacture of the derivatizedcyclodextrin, and a particular derivatized cyclodextrin will possess apreferential, although not exclusive or specific, substitution pattern.Given the above, the molecular weight of a particular derivatizedcyclodextrin composition can vary from batch to batch.

In a single parent cyclodextrin molecule, there are 3v+6 hydroxylmoieties available for derivatization. Where v=4 (α-cyclodextrin), “y”the degree of substitution for the moiety can range in value from 1 to18. Where v=5 (β-cyclodextrin), “y” the degree of substitution for themoiety can range in value from 1 to 21. Where v=6 (7-cyclodextrin), “y”the degree of substitution for the moiety can range in value from 1 to24. In general, “y” also ranges in value from 1 to 3v+g, where g rangesin value from 0 to 5. In some embodiments, “y” ranges from 1 to 2v+g, orfrom 1 to 1v+g.

The degree of substitution (“DS”) for a specific moiety (SAE, HAE or AE,for example) is a measure of the number of SAE (HAE or AE) substituentsattached to an individual cyclodextrin molecule, in other words, themoles of substituent per mole of cyclodextrin. Therefore, eachsubstituent has its own DS for an individual alkylated cyclodextrinspecies. The average degree of substitution (“ADS”) for a substituent isa measure of the total number of substituents present per cyclodextrinmolecule for the distribution of alkylated cyclodextrins within analkylated cyclodextrin composition of the present disclosure. Therefore,SAE₄-CD has an ADS (per CD molecule) of 4.

Some embodiments of the present disclosure include those wherein: 1)more than half of the hydroxyl moieties of the alkylated cyclodextrinare derivatized; 2) half or less than half of the hydroxyl moieties ofthe alkylated cyclodextrin are derivatized; 3) the substituents of thealkylated cyclodextrin are the same upon each occurrence; 4) thesubstituents of the alkylated cyclodextrin comprise at least twodifferent substituents; or 5) the substituents of the alkylatedcyclodextrin comprise one or more of substituents selected from thegroup consisting of unsubstituted alkyl, substituted alkyl, halide(halo), haloalkyl, amine (amino), aminoalkyl, aldehyde, carbonylalkyl,nitrile, cyanoalkyl, sulfoalkyl, hydroxyalkyl, carboxyalkyl, thioalkyl,unsubstituted alkylene, substituted alkylene, aryl, arylalkyl,heteroaryl, and heteroarylalkyl.

Alkylated cyclodextrin compositions can comprise multiple alkylatedcyclodextrin molecules differing in degree of substitution. For example,an alkylated cyclodextrin molecule can have 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, or more of the hydroxyl groups of the parent cyclodextrinfunctionalized with a substituent, e.g., a sulfoalkyl ether. In suchcompositions, the average degree of substitution (ADS) can becalculated, as described herein, based on the relative amounts ofalkylated cyclodextrin molecules having a particular degree ofsubstitution. As a consequence, the ADS for SAE of a SAE-CD derivativecomposition represents a weighted average of the degree of substitutionof the individual SAE-CD molecules in the composition. For example, aSAE_(5.2)-CD composition comprises a distribution of multiple SAE_(x)-CDmolecules, wherein “x” (the DS for SAE groups) can range from integershaving values of 1 to 12 for individual cyclodextrin molecules; however,the population of SAE-cyclodextrin molecules is such that the averagevalue for “x” (the ADS for SAE groups) is 5.2.

The alkylated cyclodextrin compositions can have a high to moderate tolow ADS. The alkylated cyclodextrin compositions can also have a wide ornarrow “span,” which is the number of alkylated cyclodextrin moleculeswith differing degrees of substitution within an alkylated cyclodextrincomposition. For example, an alkylated cyclodextrin compositioncomprising a single species of alkylated cyclodextrin having a singledegree of substitution is said to have a span of one, and in such acase, the degree of substitution for the alkylated cyclodextrin moleculewould equal the ADS of its alkylated cyclodextrin composition. Anelectropherogram, for example, of an alkylated cyclodextrin with a spanof one should have only one alkylated cyclodextrin species with respectto degree of substitution. An alkylated cyclodextrin composition havinga span of two comprises two individual alkylated cyclodextrin speciesdiffering in their degree of substitution, and its electropherogram, forexample, would indicate two different alkylated cyclodextrin speciesdiffering in degree of substitution. Likewise, the span of an alkylatedcyclodextrin composition having a span of three comprises threeindividual alkylated cyclodextrin species differing in their degree ofsubstitution. The span of an alkylated cyclodextrin compositiontypically ranges from 5 to 15, or 7 to 12, or 8 to 11.

A parent cyclodextrin includes a secondary hydroxyl group on the C-2 andC-3 positions of the glucopyranose residues forming the cyclodextrin anda primary hydroxyl on the C-6 position of the same. Each of thesehydroxyl moieties is available for derivatization by substituentprecursor. Depending upon the synthetic methodology employed, thesubstituent moieties can be distributed randomly or in a somewhatordered manner among the available hydroxyl positions. Theregioisomerism of derivatization by the substituent can also be variedas desired. The regioisomerism of each composition is independentlyselected. For example, a majority of the substituents present can belocated at a primary hydroxyl group or at one or both of the secondaryhydroxyl groups of the parent cyclodextrin. In some embodiments, theprimary distribution of substituents is C-3>C-2>C-6, while in otherembodiments the primary distribution of substituents is C-2>C-3>C-6.Some embodiments of the present disclosure include an alkylatedcyclodextrin molecule wherein a minority of the substituent moieties islocated at the C-6 position, and a majority of the substituent moietiesis located at the C-2 and/or C-3 position. Still other embodiments ofthe present disclosure include an alkylated cyclodextrin moleculewherein the substituent moieties are substantially evenly distributedamong the C-2, C-3, and C-6 positions.

An alkylated cyclodextrin composition comprises a distribution of pluralindividual alkylated cyclodextrin species, each species having anindividual degree of substitution (“IDS”). The content of each of thecyclodextrin species in a particular composition can be quantified usingcapillary electrophoresis. The method of analysis (capillaryelectrophoresis, for example, for charged alkylated cyclodextrins) issufficiently sensitive to distinguish between compositions having only5% of one alkylated cyclodextrin and 95% of another alkylatedcyclodextrin from starting alkylated cyclodextrin compositionscontaining a single alkylated cyclodextrin.

The above-mentioned variations among the individual species of alkylatedcyclodextrins in a distribution can lead to changes in the complexationequilibrium constant K1:1 which in turn will affect the required molarratios of the derivatized cyclodextrin to active agent. The equilibriumconstant is also somewhat variable with temperature and allowances inthe ratio are required such that the agent remains solubilized duringthe temperature fluctuations that can occur during manufacture, storage,transport, and use. The equilibrium constant can also vary with pH andallowances in the ratio can be required such that the agent remainssolubilized during pH fluctuations that can occur during manufacture,storage, transport, and use. The equilibrium constant can also vary duethe presence of other excipients (e.g., buffers, preservatives,antioxidants). Accordingly, the ratio of derivatized cyclodextrin toactive agent can be varied from the ratios set forth herein in order tocompensate for the above-mentioned variables.

The alkylated cyclodextrins made according to a process of the presentdisclosure can be employed in compositions, formulations, methods andsystems as such those disclosed in U.S. Pat. Nos. 5,134,127, 5,376,645,5,914,122, 5,874,418, 6,046,177, 6,133,248, 6,153,746, 6,407,079,6,869,939, 7,034,013, 7,625,878, 7,629,331, 7,635,773, 9,493,582, and10,040,872; U.S. Pub. Nos. 2005/0164986, 2005/0186267, 2005/0250738,2006/0258537, 2007/0020196, 2007/0020298, 2007/0020299, 2007/0175472,2007/0202054, 2008/0194519, 2009/0011037, 2009/0012042, 2009/0123540;U.S. application Ser. Nos. 12/404,174, 12/407,734, 61/050,918,61/177,718, and 61/182,560; and PCT International Application Nos.PCT/US06/62346, PCT/US07/71758, PCT/US07/71748, PCT/US07/72387,PCT/US07/72442, PCT/US07/78465, PCT/US08/61697, PCT/US08/61698,PCT/US08/70969, and PCT/US08/82730, the entire disclosures of which arehereby incorporated by reference. The alkylated cyclodextrins preparedaccording to the processes herein can also be used as suitablesubstitutes for other known grades of alkylated cyclodextrins possessingthe same functional groups.

In some embodiments, an alkylated cyclodextrin possesses greater watersolubility than a corresponding cyclodextrin from which an alkylatedcyclodextrin composition of the present disclosure is prepared. Forexample, in some embodiments, an underivatized cyclodextrin is utilizedas a starting material, e.g., α-, β- or γ-cyclodextrin, commerciallyavailable from, e.g., WACKER BIOCHEM CORP. (Adrian, MI), and othersources. Underivatized cyclodextrins have limited water solubilitycompared to the alkylated cyclodextrins compositions of the presentdisclosure. For example, underivatized α-CD, β-CD, γ-CD have asolubility in water solubility of about 145 g/L, 18.5 g/L, and 232 g/L,respectively, at saturation.

The water-soluble alkylated cyclodextrin composition is optionallyprocessed to remove a major portion (e.g., >50%) of an underivatizedcyclodextrin, or other contaminants.

The terms “alkylene” and “alkyl,” as used herein (e.g., in the—O—(C₂-C₆-alkylene)SO₃ ⁻ group or in the alkylamine cations), includelinear, cyclic, and branched, saturated and unsaturated (i.e.,containing one or more double bonds), divalent alkylene groups andmonovalent alkyl groups, respectively. For example, SAE or HAE moietiescan have the same type or different type of alkylene (alkyl) radicalupon each occurrence in an alkylated cyclodextrin composition. In suchembodiments, the alkylene radical in the SAE or HAE moiety can be ethyl,propyl, butyl, pentyl or hexyl in each occurrence in an alkylatedcyclodextrin composition.

The term “alkanol” in this text likewise includes both linear, cyclicand branched, saturated and unsaturated alkyl components of the alkanolgroups, in which the hydroxyl groups can be situated at any position onthe alkyl moiety. The term “cycloalkanol” includes unsubstituted orsubstituted (e.g., by methyl or ethyl) cyclic alcohols.

In some embodiments, the present disclosure provides an alkyl ethercyclodextrin (AE-CD) composition, comprising an alkyl ether cyclodextrinhaving an average degree of substitution of 2 to 9, and less than 0.1%(w/w) of a chloride. In some embodiments, the present disclosureprovides an AE-CD composition, comprising an alkyl ether cyclodextrinhaving an average degree of substitution of 2 to 9, and less than 0.05%(w/w) of a chloride. In some embodiments, the present disclosureprovides an AE-CD composition, comprising an alkyl ether cyclodextrinhaving an average degree of substitution of 2 to 9, and less than 0.01%(w/w) of a chloride. In some embodiments, the present disclosureprovides an AE-CD composition, comprising an alkyl ether cyclodextrinhaving an average degree of substitution of 2 to 9, and less than 0.002%(w/w) of a chloride. In some embodiments, the alkyl ether cyclodextrincomposition is not a sulfobutyl ether cyclodextrin composition. In someembodiments, the alkyl ether cyclodextrin is not a sulfobutyl etherβ-cyclodextrin.

In some embodiments, the average degree of substitution of the AE-CD is4.5 to 7.5. In some embodiments, the average degree of substitution ofthe AE-CD is 6 to 7.5. In some embodiments, the average degree ofsubstitution of the AE-CD is 6.2 to 6.9.

In some embodiments, the present disclosure provides a compositioncomprising an AE-CD and an active agent.

In some embodiments, the present disclosure provides a sulfoalkyl ethercyclodextrin (SAE-CD) composition comprising a sulfoalkyl ethercyclodextrin having an average degree of substitution of 2 to 9, andless than 0.1% (w/w) of a chloride. In some embodiments, the presentdisclosure provides a SAE-CD composition comprising a sulfoalkyl ethercyclodextrin having an average degree of substitution of 2 to 9, andless than 0.05% (w/w) of a chloride. In some embodiments, the presentdisclosure provides a SAE-CD composition, comprising a sulfoalkyl ethercyclodextrin having an average degree of substitution of 2 to 9, andless than 0.01% (w/w) of a chloride. In some embodiments, the presentdisclosure provides a SAE-CD composition, comprising a sulfoalkyl ethercyclodextrin having an average degree of substitution of 2 to 9, andless than 0.002% (w/w) of a chloride.

In some embodiments, the sulfoalkyl ether cyclodextrin is a compound ofFormula (II):

wherein p is 4, 5, or 6, and R₁ is independently selected at eachoccurrence from —OH or —O—(C₂-C₆ alkylene)-SO₃ ⁻-T, wherein T isindependently selected at each occurrence from pharmaceuticallyacceptable cations, provided that at least one R₁ is —OH and at leastone R₁ is O—(C₂-C₆ alkylene)-SO₃ ⁻-T. In some embodiments, R₁ isindependently selected at each occurrence from —OH or —O—(C₄alkylene)-SO₃ ⁻-T, and -T is Na⁺ at each occurrence.

In some embodiments, T may be associated with an ion exchange resin,poly-L-lysine, polycationic chitosan, or any combination thereof.

In some embodiments, the average degree of substitution of the SAE-CD is4.5 to 7.5. In some embodiments, the average degree of substitution ofthe SAE-CD is 6 to 7.5. In some embodiments, the average degree ofsubstitution of the SAE-CD is 6.2 to 6.9.

In some embodiments, the present disclosure provides a compositioncomprising a SAE-CD and an active agent.

The present disclosure describes several methods for preparing analkylated cyclodextrins. In general, an underivatized cyclodextrinstarting material in neutral to alkaline aqueous media is exposed tosubstituent precursor. The substituent precursor can be addedincrementally or as a bolus, and the substituent precursor can be addedbefore, during, or after exposure of the cyclodextrin starting materialto the optionally alkaline aqueous media. Additional alkaline materialor buffering material can be added as needed to maintain the pH within adesired range. The derivatization reaction can be conducted at ambientto elevated temperatures. Once derivatization has proceeded to thedesired extent, the reaction is optionally quenched by addition of anacid. The reaction milieu is further processed (e.g., solventprecipitation, filtration, centrifugation, evaporation, concentration,drying, chromatography, dialysis, and/or ultrafiltration) to removeundesired materials and form the target composition. After finalprocessing, the composition can be in the form of a solid, liquid,semi-solid, gel, syrup, paste, powder, aggregate, granule, pellet,compressed material, reconstitutable solid, suspension, glass,crystalline mass, amorphous mass, particulate, bead, emulsion, or wetmass.

The disclosure provides a process of making an alkylated cyclodextrin,optionally having a pre-determined degree of substitution, the processcomprising: combining an unsubstituted cyclodextrin starting materialwith an alkylating agent in an amount sufficient to effect thepre-determined degree of substitution, in the presence of an alkalimetal hydroxide; conducting alkylation of the cyclodextrin within a pHof 9 to 11 until residual unreacted cyclodextrin is less than 0.5% byweight, or less than 0.1%; adding additional hydroxide in an amountsufficient to achieve the degree of substitution and allowing thealkylation to proceed to completion; and adding additional hydroxide todestroy any residual alkylating agent.

Adding an additional hydroxide can be conducted using a quantity ofhydroxide, and under conditions (i.e., amount of additional hydroxideadded, temperature, length of time during which the alkylating agenthydrolysis is conducted) such that the level of residual alkylatingagent in the aqueous crude product is reduced to less than 20 ppm orless than 2 ppm.

It is possible that the reaction milieu or the partially purifiedaqueous solution will comprise unreacted alkylating agent. Thealkylating agent can be degraded in situ by adding additional alkalizingagent or by heating a solution containing the agent. Degrading an excessalkylating agent will be required where unacceptable amounts ofalkylating agent are present in the reaction milieu followingtermination of the mixing. The alkylating agent can be degraded in situby adding additional alkalizing agent or by heating a solutioncontaining the agent.

Degrading can be conducted by: exposing the reaction milieu to anelevated temperature of at least 60° C., at least 65° C., or 60° C. to85° C., 60° C. to 80° C., or 60° C. to 95° C. for a period of at least 6hours, at least 8 hours, 8 hours to 12 hours, 6 hours to 72 hours, or 48hours to 72 hours, thereby degrading the alkylating agent in situ andreducing the amount of or eliminating the alkylating agent in theaqueous liquid.

After the reaction has been conducted as described herein, the aqueousmedium containing the alkylated cyclodextrin can be neutralized to a pHof 7 in order to quench the reaction. The solution can then be dilutedwith water in order to lower viscosity, particularly if furtherpurification is to be conducted. Further purifications can be employed,including, but not limited to, diafiltration on an ultrafiltration unitto purge the solution of reaction by-products such as salts (e.g., NaClif sodium hydroxide was employed as the base) and other low molecularweight by-products. The product can further be concentrated byultrafiltration. The product solution can then be treated with activatedcarbon in order to improve its color, reduce bioburden, andsubstantially remove one or more drug degrading impurities. The productcan be isolated by a suitable drying technique such as freeze drying,spray drying, or vacuum drum drying.

The reaction can initially be prepared by dissolving an unsubstitutedα-, β-, or γ-cyclodextrin starting material in an aqueous solution ofbase, usually a hydroxide such as lithium, sodium, or potassiumhydroxide. The base may be present in a catalytic amount (i.e., a molarratio of less than 1:1 relative to the cyclodextrin), to achieve apre-determined or desired degree of substitution. That is, the base maybe present in an amount less than one molar equivalent for each hydroxylsought to be derivatized in the cyclodextrin molecule. Becausecyclodextrins become increasingly soluble in aqueous solution as thetemperature is raised, the aqueous reaction mixture containing base andcyclodextrin can be raised to a temperature of 50° C. to ensure completedissolution. Agitation is generally employed throughout the course ofthe alkylation reaction.

After dissolution is complete, the alkylating agent is added to startthe alkylation reaction. The total amount of alkylating agent addedthroughout the reaction will generally be in excess of thestoichiometric amount required to complete the reaction relative to theamount of cyclodextrin, since some of the alkylating agent is hydrolyzedand/or otherwise destroyed/degraded during the reaction such that it isnot available for use in the alkylation reaction. The exact amount ofalkylating agent to use for a desired degree of substitution can bedetermined through the use of trial runs. The entire amount ofalkylating agent needed to complete the reaction can be added prior toinitiating the reaction. Because the system is aqueous, the reaction isgenerally conducted at a temperature between 50° C. and 100° C. Thereaction can be conducted at a temperature less than 100° C., so thatspecialized pressure equipment is not required. In general, atemperature of 65° C. to 95° C. is suitable.

During the initial phase of the reaction (herein referred to as thepH-control phase), care should be taken to monitor the pH and maintainit at least basic, or in at a pH of 8 to 11. Monitoring of pH can beeffected conventionally as by using a standard pH meter. Adjustment ofthe pH can be effected by adding an aqueous solution of hydroxide, e.g.,a 10-15% solution. During the initial pH-control phase, unreactedcyclodextrin is reacted to the extent that less than 0.5% by weight, orless than 0.1% by weight, of unreacted cyclodextrin remains in solution.Substantially the entire initial charge of cyclodextrin is thus reactedby being partially substituted, but to less than the desiredpre-determined degree of substitution. Residual cyclodextrin can bemonitored throughout this initial phase, for example by HPLC asdescribed below, until a desired endpoint of less than 0.5%, or lessthan 0.1%, of residual cyclodextrin starting material, has beenachieved. The pH can be maintained and/or raised by adding concentratedhydroxide to the reaction medium continuously or in discrete amounts assmall increments. Addition in small increments is particularly suitable.

Once an alkylation procedure has been standardized or optimized so thatit is known that particular amounts of reactants can be combined in aprocedure which produces the desired degree of substitution inconjunction with low residual cyclodextrin, then the procedure cansimply be checked at the end, as opposed to throughout or during theinitial pH-control, to ensure that a low level of residual (unreacted)cyclodextrin starting material has been achieved. The following tablesets forth a relationship between the amount of butane sultone chargedinto a reactor and the resulting average degree of substitution of theSAE-CD.

Butane Sultone Charged Corresponding Approximate (Approximateequivalents of Predetermined ADS for BS per mole of cyclodextrin) SAE-CDformed 2 2 3 3 4 4 5 5 6  5-5.5 7 5.5 to 6.5 8 6.5 to 7   9 7-8 12 8-9

It is noted that the initial pH of the reaction medium can be above 11,for example after combining the initial charge of cyclodextrin startingmaterial and base, but prior to addition of alkylating agent. After analkylating agent has been added and the reaction commences, however, thepH quickly drops, necessitating addition of base to maintain a basic pHof about 8 to about 11.

Once the level of residual unreacted cyclodextrin has reached a desiredlevel, e.g., below 0.5% by weight, during the pH control stage, the pHcan be raised to above 11, for example a level above 12, by addingadditional base to drive the reaction to completion. The pH can be atleast 12 so that the reaction proceeds at a reasonable rate, but not sohigh that unreacted alkylating agent is hydrolyzed rapidly rather thanreacting with cyclodextrin. During this latter phase of the reaction,additional substitution of the cyclodextrin molecule is effected untilthe pre-determined degree of substitution has been attained. The totalamount of hydroxide added throughout the reaction is typically on theorder of the amount stoichiometrically required plus a 10-20% molarexcess relative to the amount of alkylating agent employed. The additionof more than a 10-20% excess is also feasible. The reaction end point,as noted above, can be detected by HPLC. A suitable temperature is 65°C. to 95° C. The HPLC system typically employs an anion exchangeanalytical column with pulsed amperometric detection (PAD). Elution canbe by gradient using a two-solvent system, e.g., Solvent A being 25 mM(millimolar) aqueous sodium hydroxide, and Solvent B being 1 M sodiumnitrate in 250 mM sodium hydroxide.

Once the alkylation reaction is complete and the low residualcyclodextrin end point has been reached, additional hydroxide can beadded to destroy and/or degrade any residual alkylating agent. Theadditional hydroxide is typically added in an amount of 0.5 to 3 molarequivalents relative to cyclodextrin, and the reaction medium is allowedto continue heating at 65° C. to 95° C., typically for 6 hours to 72hours.

After residual alkylating agent destruction, the resulting crude productcan be additionally treated to produce a final product by being diluted,diafiltered to reduce or rid the product of low molecular weightcomponents such as salts, concentrated, carbon treated, and dried.

The pH is initially monitored to ensure that it remains at 8 to 11 asthe alkyl derivatization reaction proceeds. In this initial stage,addition of a hydroxide to facilitate the alkylation can be staged orstep-wise. Monitoring the pH of the reaction ensures that the reactioncan be controlled such that the entire initial stock of cyclodextrinstarting material is essentially reacted to the extent of effecting, onaverage, at least one alkyl substitution per cyclodextrin molecule. Theentire cyclodextrin reactant is thus consumed at the beginning of theprocess, so that the level of residual (unreacted) cyclodextrin in thecrude product is low, relative to the crude product produced by aprocess which features initially combining the entire stoichiometric orexcess amount of base with cyclodextrin and alkylating agent andallowing the reaction to proceed uncontrolled. After the entire chargeof cyclodextrin starting material has been partially reacted, theremaining hydroxide can be added to drive the reaction to completion byfinishing the alkyl substitution to the pre-determined, desired degree.After the initial charge of cyclodextrin has been consumed in the firstpH-controlled phase, the rate of hydroxide addition is not critical.Thus, the hydroxide can be added (e.g., as a solution) continuously orin discrete stages. In addition, the pH of the reaction medium should bemaintained above about 12 so that the rate of reaction is commerciallyuseful. Additional methods for making alkylated cyclodextrins aredescribed in U.S. Pat. No. 9,751,957, the disclosure of which is herebyincorporated by reference in its entirety.

Process for Removal of Impurities from Alkylated Cyclodextrin

The present disclosure provides a process for preparing an alkylatedcyclodextrin composition, the process comprising: (a) mixing acyclodextrin with an alkylating agent to form a reaction milieucomprising an alkylated cyclodextrin; (b) conducting a first one or moreseparations to form a first solution comprising the alkylatedcyclodextrin, wherein the one of more separations comprisesdiafiltration through a first membrane; (c) treating the first solutionwith an activated carbon to produce a second alkylated cyclodextrinsolution; and (d) conducting a second one or more separations to form athird alkylated cyclodextrin solution, wherein the one or moreseparations comprises nanofiltration through a second membrane. In someembodiments, the first membrane is an ultrafiltration membrane. In someembodiments, the second membrane is a nanofiltration membrane.

FIG. 1 provides a schematic representation of a process of the instantdisclosure. In the first step (100), a reaction milieu comprising crudealkylated cyclodextrin is formed. In some embodiments, the reactionmilieu of step (a) containing the crude alkylated cyclodextrin ispurified by diafiltration and/or ultrafiltration (102), processes inwhich the crude product is contacted with a semipermeable membrane thatpasses low molecular weight impurities through the membrane. Thefiltration membrane can include nylon, TEFLON®, PVDF or anothercompatible material.

The molecular weight of the impurities passed through the membranedepends on the molecular weight cut-off (MWCO) for the membrane and canbe varied as needed according to the particle size or molecular weightof species being separated from the alkylated cyclodextrin in a solutioncontaining the same. For the instant disclosure, a membrane having amolecular weight cutoff of 1,000 Daltons (“Da”) is typically employed.Diafiltrations and/or ultrafiltrations can be conducted with filtrationmembranes having a molecular weight cut-off of 500 Da to 2,000 Da, 500Da to 1,500 Da, 750 Da to 1,250 Da, or 900 Da to 1,100 Da, or about1,000 Da. For example, in some embodiments, the filtration membrane mayhave a MWCO of about 500 Da, 550 Da, 600 Da, 650 Da, 700 Da, 750 Da, 800Da, 850 Da, 900 Da, 950 Da, 1,000 Da, 1050 Da, 1100 Da, 1150 Da, 1200Da, or 1250 Da.

In some embodiments, the reaction milieu of step (a) is optionallydiluted with solvent prior to the first one or more separations bydiafiltration (102). In some embodiments the solvent is water. Thereaction milieu is diluted to achieve a desired concentration ofalkylated cyclodextrin in solution prior to the one or more separations.For example, in some embodiments, the concentration of alkylatedcyclodextrin in the reaction milieu immediately prior to conducting thefirst one or more separations by diafiltration may be less than 10%(w/w), less than 9% (w/w), less than 8% (w/w), less than 7% (w/w), lessthan 6% (w/w), less than 5% (w/w), less than 4% (w/w). In someembodiments, the concentration of the alkylated cyclodextrin in thereaction milieu immediately prior to conducting the first one or moreseparations by diafiltration may be about 1% (w/w), 2% (w/w), 3% (w/w),4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), or 9% (w/w). In someembodiments, the concentration of the alkylated cyclodextrin in thereaction milieu immediately prior to conducting the first one or moreseparations by diafiltration may be from 2% (w/w) to 9% (w/w), from 3%(w/w) to 8% (w/w), from 5% (w/w) to 8% (w/w), or from 4% (w/w) to 6%(w/w).

The solution obtained after diafiltration may be further treated withactivated carbon to substantially remove impurities (104). A widevariety of activated carbon is available. For example, Norit-Americascommercializes over 150 different grades and varieties of activatedcarbon under trademarks such as DARCO®, HYDRODARCO®, NORIT®,BENTONORIT®, PETRODARCO®, and SORBONORIT®. The carbons differ inparticle size, application, method of activation, and utility. Forexample, some activated carbons are optimized for color and/or flavorremoval. Other activated carbons are optimized for removal of protein,mineral, and/or amino acid moieties, or for clarifying solutions.

Activated carbon suitable for use in the process of the presentdisclosure can be phosphate-free, and can be powder or granular, or asuspension or slurry produced therefrom. Generally, phosphate-freeactivated carbon is a carbon that was not activated using, or otherwiseexposed to, phosphoric acid. In some embodiments, the activated carbonused in the processes described herein is phosphate free. In someembodiments the activated carbon used in the processes described hereinis granular. In some embodiments the activated carbon used in theprocesses described herein is steam activated.

Activated carbons suitable for use according to the present disclosureinclude, but are not limited to: DARCO® 4×12, 12×20, or 20×40 granularfrom lignite, steam activated (Norit Americas, Inc., Amersfoort, NE);DARCO® S 51 HF (from lignite, steam activated, powder); SHIRASAGI® DC-32powered or granular carbon from wood, zinc chloride activated (TakedaChemical Industries, Ltd., Osaka, JP); and various ColorSorb™ granularactivated carbons from mineral or coconut shell, steam activatedincluding, but not limited to, ColorSorb™ 5000, ColorSorb™ H150-LC,ColorSorb™ H620, ColorSorb™ HS, and ColorSorb™ HS-D (Jacobi CarbonsFrance SASU). In some embodiments, that activated carbon used in theprocesses described herein can be prepared for use using the CarbonPreparation Process described below.

The loading ratio of activated carbon ultimately depends upon the amountor concentration of the alkylated cyclodextrin and impurities insolution as well as the physical properties of the activated carbonused. In general, the weight ratio of a cyclodextrin to activated carbonis 5:1 to 10:1, 6:1 to 9:1, 7:1 to 9:1, 8:1 to 9:1, 8.3:1 to 8.5:1,8.4:1 to 8.5:1, or 8.44:1 by weight per treatment cycle.

As used herein, “treatment cycle” refers to a contacting a predeterminedamount of a cyclodextrin composition with a predetermined amount ofactivated carbon. A treatment cycle can be performed as a singletreatment or as a multiple (recycling) pass-through treatment. In someembodiments, the alkylated cyclodextrin solution obtained afterdiafiltration may be subjected to a treatment cycle wherein thealkylated cyclodextrin solution is passed through (recycled) through theactivated carbon for 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5hours, 6 hours, or more. In some embodiments, after the first treatmentcycle is completed, the alkylated cyclodextrin solution may be subjectedto a second treatment cycle wherein the alkylated cyclodextrin solutionis passed through (recycled) through the activated carbon for 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more.

The alkylated cyclodextrin solution produced after carbon treatment maybe further purified by nanofiltration through a nanofiltration membrane(106). Nanofiltration membranes generally have pore sizes ranging from0.1 nm to 10 nm, where are smaller than those used in diafiltration andultrafiltration. For example, nanofiltration membranes suitable for usein the processes of the present disclosure have pore sizes of 0.1 nm,0.2 nm, 0.3 nm, 0.4 nm, 0.5 nm, 0.6 nm, 0.7 nm, 0.8 nm, 0.9 nm, 1.0 nm,1.5 nm, 2.0 nm, 2.5 nm, 3.0 nm, 3.5 nm, 4.0 nm, 4.5 nm, 5.0 nm, 5.5 nm,6.0 nm, 6.5 nm, 7.0 nm, 7.5 nm, 8.0 nm, 8.5 nm, 9.0 nm, 9.5 nm, or 10nm, or within a range defined by any of the foregoing pore sizes, suchas 1.0 to 10 nm, 1.0 nm to 5 nm, 0.1 nm to 5 nm, 0.5 nm to 5 nm, or 0.5nm to 2.0 nm. The nanofiltration membranes suitable for use in theprocesses of the present disclosure generally have a MWCO of about 500Da, for example, 150 Da to 500 Da, 200 Da to 500 Da, 300 Da to 500 Da,300 Da to 600 Da, or 200 Da to 600 Da. In some embodiments, thenanfiltration membrane may have a MWCO of about 100 Da, 150 Da, 200 Da,250 Da, 300 Da, 350 Da, 400 Da, 450 Da, 500 Da, 550 Da, or 600 Da.

The nanofiltration step may be conducted one or more times and for aperiod for anywhere between 30 minutes to about 24 hours, 30 minutes to12 hours, 1 hour to 10 hours, 1 hour to 4 hours, 1 hour to 3 hours, orany other suitable period. For example, in some embodiments, thenanofiltration may be conducted for a period of 30 minute, 1 hour, 1.5hours, 2 hours, 3, hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours or more.

In some embodiments, nanofiltration results in an alkylated cyclodextrinsolution that is more concentrated than the alkylated cyclodextrinsolution obtained immediately after treatment with activated carbon. Insome embodiments, the concentration of the alkylated cyclodextrin in thesolution obtained after nanofiltration may be from about 10% (w/w) toabout 30% (w/w), from about 10% (w/w) to about 25% (w/w), from about 15%(w/w) to about 30% (w/w), from about 15% (w/w) to about 25% (w/w), fromabout 15% (w/w) to about 20% (w/w), from about 18% (w/w) to about 25%(w/w), or from about 18% (w/w) to about 20% (w/w). For example, theconcentration of the alkylated cyclodextrin in the solution obtainedafter nanofiltration may be about 10% (w/w), 11% (w/w), 12% (w/w), 13%(w/w), 14% (w/w), 15% (w/w), 16% (w/w), 17% (w/w), 18% (w/w), 19% (w/w),20% (w/w), 21% (w/w), 22% (w/w), 23% (w/w), 24% (w/w), 25% (w/w), 26%(w/w), 27% (w/w), 28% (w/w), 29% (w/w), or 30% (w/w).

After nanofiltration is complete, the resulting alkylated cyclodextrinsolution may be further concentrated to prepare for recovery of solidalkylated cyclodextrin (108). The alkylated cyclodextrin solution fromthe nanofiltration may be further concentrated to produce an alkylatedcyclodextrin solution wherein the concentration of alkylatedcyclodextrin is from about 30% (w/w) to about 70% (w/w), from about 40%(w/w) to about 60% (w/w), or about 50% (w/w). In some embodiments, thealkylated cyclodextrin solution resulting from the nanofiltration stepis concentrated for a period of about 2 to about 24 hours, about 6 toabout 18 hours, or about 8 to about 12 hours. In some embodiments, thealkylated cyclodextrin solution resulting from the nanofiltration stepis concentrated for a period of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In someembodiments, the alkylated cyclodextrin solution resulting from thenanofiltration step is concentrated by removing the solvent viadistillation. In some embodiments, the alkylated cyclodextrin solutionresulting from the nanofiltration step is concentrated by removing thesolvent via lyophilization. In some embodiments, the alkylatedcyclodextrin solution resulting from the nanofiltration step isconcentrated using standard methods known in the art.

A final, solid alkylated cyclodextrin product can be isolated at thispoint by evaporation of the solvent (via, e.g., distillation, spraydying, lyophilization, and the like) (110). The final product producedby the instant disclosure advantageously contains very low residuallevels of alkylating agent, e.g., less than 2 ppm based on the weight ofthe dry (i.e., containing less than 10% by weight water) final product,less than 1 ppm, less than 250 ppb, or essentially no residualalkylating agent. The final product containing less than 250 ppb ofalkylating agent is accordingly provided as an additional feature of thedisclosure. The alkylating agent can be reduced following completion ofthe alkylation to the desired degree of substitution by an alkalinehydrolysis treatment as previously described, i.e., by adding extrahydroxide solution in an amount and under conditions sufficient toreduce the amount of unreacted alkylating agent in the dry product tothe desired level below 2 ppm, less than 1 ppm, or less than 250 ppb.

In some embodiments, the phosphate level of the solid alkylatedcyclodextrin is less than 500 ppm, less than 200, less than 150 ppm,less than 125 ppm, less than 100 ppm, less than 95 ppm, less than 90ppm, less than 85 ppm, less than 80 ppm, less than 75 ppm, less than 70ppm, less than 65 ppm, less than 60 ppm, less than 55 ppm, less than 50ppm, less than 45 ppm, less than 40 ppm, less than 35 ppm, less than 30ppm, less than 25 ppm, less than 20 ppm, less than 15 ppm, less than 10ppm, or less than 5 ppm. In some embodiments, the phosphate level in thesolid alkylated cyclodextrin composition is 200 ppm to 5 ppm, 150 ppm to5 ppm, 125 ppm to 5 ppm, 100 ppm to 5 ppm, 75 ppm to 5 ppm, 50 ppm to 5ppm, 150 ppm to 10 ppm, 125 ppm to 10 ppm, 100 ppm to 10 ppm, or 75 ppmto 10 ppm.

In some embodiments, the compositions of the present invention aresubstantially free of one or more UV-active impurities. In someembodiments, the UV-active impurities may be a drug-degrading agent. Thepresence of one or more UV-active impurities can be determined, interalia, by UV/visible (“UV/vis”) spectrophotometry. As used herein, a“drug degrading agent” or “drug degrading impurity” refers to a species,moiety, and the like, that degrades certain active components in aqueoussolution. It will be understood that a drug degrading agent may notdegrade all drugs with which an alkylated cyclodextrin composition maybe combined, depending on the chemical structure of the drug and itsdegradation pathways. In some embodiments, a drug-degrading species hasan absorption in the UV/visible region of the spectrum, for example, anabsorption maximum at a wavelength of 245 nm to 270 nm.

The alkylated cyclodextrin composition can be measured by UV/vis inabsorbance units (A.U.). In some embodiments, the alkylated cyclodextrincomposition has an absorption of less than 1 A.U., less than 0.9 A.U.,less than 0.8 A.U., less than 0.7 A.U., less than 0.6 A.U., 0.5 A.U.,less than 0.4 A.U., less than 0.3 A.U., less than 0.2 A.U., or less than0.1 A.U. In some embodiments, the presence of UV-active agents in thecomposition can be measured by UV/vis in absorbance units.

The absorbance of the solution becomes linear with the concentrationaccording to the formula:

-   -   A=εlc    -   wherein    -   A=absorbance    -   ε=extinction coefficient    -   l=path length    -   c=molar concentration.

The alkylated cyclodextrin composition can be measured using UV/visspectrophotometry at a wavelength of 245 to 270 nm using a cell having apath length of 1 cm. In some embodiments, the alkylated cyclodextrincomposition has an absorption of less than 1 A.U. at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, less than 1 A.U. at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, less than1 A.U. at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, less than 1 A.U. at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.9 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, 0.9 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, 0.9 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.9 A.U. or less at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.8 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, 0.8 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, 0.8 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.8 A.U. or less at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.7 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, 0.7 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, 0.7 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.7 A.U. or less at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.6 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, 0.6 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, 0.6 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.6 A.U. or less at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.5 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, 0.5 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, 0.5 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.5 A.U. or less at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.4 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition per mL of solution, 0.4 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 300 mgof the alkylated cyclodextrin composition per mL of solution, 0.4 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 400 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.4 or less A.U. at a wavelength of 245 nm to 270 nm for anaqueous solution containing 500 mg of the alkylated cyclodextrincomposition per mL of solution, 0.3 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 200 mg of the alkylatedcyclodextrin composition, 0.3 A.U. or less at a wavelength of 245 nm to270 nm for an aqueous solution containing 300 mg of the alkylatedcyclodextrin composition per mL of solution, 0.3 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 400 mgof the alkylated cyclodextrin composition per mL of solution, 0.3 A.U.or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 500 mg of the alkylated cyclodextrin composition per mL ofsolution, 0.2 A.U. or less at a wavelength of 245 nm to 270 nm for anaqueous solution containing 200 mg of the alkylated cyclodextrincomposition per mL of solution, 0.2 A.U. or less at a wavelength of 245nm to 270 nm for an aqueous solution containing 300 mg of the alkylatedcyclodextrin composition per mL of solution, 0.2 A.U. or less at awavelength of 245 nm to 270 nm for an aqueous solution containing 400 mgof the alkylated cyclodextrin composition per mL of solution, or 0.2A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solutioncontaining 500 mg of the alkylated cyclodextrin composition per mL ofsolution. In some embodiments, the presence of impurities in thealkylated cyclodextrin compositions can be measured by UV/vis inabsorbance units.

The impurities components can include, but are not limited to, lowmolecular weight impurities (i.e., impurities having a molecular weightof about 500 Da or less), water-soluble and/or water-insoluble ions(i.e., salts), hydrolyzed sulfoalkylating agent,5-(hydroxymethyl)-2-furaldehyde, unreacted cyclodextrin startingmaterial, degraded cyclodextrin species (e.g., degraded and/orring-opened species formed from unreacted cyclodextrin, partiallyreacted cyclodextrin, and/or SAE-CD), unreacted alkylating agent (e.g.,1,4-butane sultone), and combinations thereof.

Not being bound by any particular theory, a UV-active agent, species, ormoiety can include one or more low-molecular weight species (e.g., aspecies having a molecular weight less than 1,000 Da), such as, but notlimited to a species generated as a side-product and/or decompositionproduct in the reaction mixture. As such, UV-active species include, butare not limited to, a glycosidic moiety, a ring-opened cyclodextrinspecies, a reducing sugar, a glucose degradation product (e.g.,3,4-dideoxyglucosone-3-ene, carbonyl-containing degradants such as2-furaldehyde, 5-hydroxymethyl-2-furaldehyde and the like), andcombinations thereof.

In some embodiments, the solid alkylated cyclodextrin comprises lessthan 1% wt., less than 0.5% wt., less than 0.2% wt., less than 0.1% wt.,less than 0.09% wt., less than 0.08% wt., less than 0.07% wt., less than0.06% wt., less than 0.05% wt., less than 0.04% wt., less than 0.03%wt., less than 0.02% wt., less than 0.01% wt., less than 0.009% wt.,less than 0.008% wt., less than 0.007% wt., less than 0.005% wt., orless than 0.002% wt. of an alkali metal halide salt.

In some embodiments, the solid alkylated cyclodextrin comprises lessthan 1% wt., less than 0.5% wt., less than 0.2% wt., less than 0.1% wt.,less than 0.09% wt., less than 0.08% wt., less than 0.07% wt., less than0.06% wt., less than 0.05% wt., less than 0.04% wt., less than 0.03%wt., less than 0.02% wt., less than 0.01% wt., less than 0.009% wt.,less than 0.008% wt., less than 0.007% wt., less than 0.005% wt., orless than 0.002% wt. of chloride.

In some embodiments, the solid alkylated cyclodextrin comprises lessthan 1% wt., less than 0.5% wt., less than 0.25% wt., less than 0.1%wt., less than 0.08% wt., or less than 0.05% wt. of a hydrolyzedalkylating agent.

In some embodiments, the solid alkylated cyclodextrin comprises lessthan 500 ppm, less than 100 ppm, less than 50 ppm, less than 20 ppm,less than 10 ppm, less than 5 ppm, less than 2 ppm, less than 1 ppm,less than 500 ppb, or less than 250 ppb of an alkylating agent.

In some embodiments, the solid alkylated cyclodextrin comprises lessthan 0.5% wt., less than 0.2% wt., less than 0.1% wt., or less than0.08% wt. of underivatized cyclodextrin.

The chloride level of the alkylated cyclodextrin can be determined usingany method commonly used by one of skill in the art. In someembodiments, the chloride level is measured using charged aerosoldetection (CAD). In some embodiments, the chloride level is measuredusing ion chromatography.

In some embodiments, the chloride level as measured by weight ratio(w/w) of the alkylated cyclodextrin is 1% or less, 0.9% or less, 0.8% orless, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% orless, 0.2% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% orless, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02%or less, 0.01% or less, 0.009% or less, 0.008% or less, 0.007% or less,0.006% or less, 0.005% or less, 0.004% or less, 0.003% or less, or0.002% or less. In some embodiments, the chloride level in the alkylatedcyclodextrin is 1% to 0.002%, 0.9% to 0.002%, 0.8% to 0.002%, 0.7% to0.002%, 0.6% to 0.002%, 0.5% to 0.002%, 0.4% to 0.002%, 0.3% to 0.002%,0.2% to 0.002%, 0.1% to 0.002%, 0.09% to 0.002%, 0.08% to 0.002%, 0.07%to 0.002%, 0.06% to 0.002%, 0.05% to 0.002%, 0.04% to 0.002%, 0.03% to0.002%, 0.02% to 0.002%, 0.01% to 0.002%, 0.009% to 0.002%, 0.008% to0.002%, 0.007% to 0.002%, 0.006% to 0.002%, 0.005% to 0.002%. 0.004% to0.002%, or 0.003% to 0.002%.

The final yield of the alkylated cyclodextrin (in isolated and/orpurified or partially purified form) obtained at completion of theprocess will vary. The final yield of alkylated cyclodextrin based onthe cyclodextrin starting material can range from 10% to 95%, 15% to90%, 20% to 85%, 30% to 85%, 35% to 85%, 40% to 85%, 45% to 80%, 50% to80%, 55% to 80%, 60% to 80%, 50% to 90%, 55% to 90%, 60% to 90%, 70% to90%, 80% to 90%, 60% to 98%, 70% to 98%, 80% to 98%, or 90% to 98%. Insome embodiments, the final yield of alkylated cyclodextrin based on thecyclodextrin starting material is 80% or greater, 85% or greater, 90% orgreater, or 95% or greater.

The processes of the instant disclosure are suitable for large-scaleproduction and purification of alkylated cyclodextrin and present amarked increase from previously known processes. The processes describedherein may be used to prepare single batches of alkylated cyclodextrinusing greater than 275 kg of a starting cyclodextrin (e.g.,α-cyclodextrin, β-cyclodextrin, or 7-cyclodextrin). In some embodiments,the starting cyclodextrin is β-cyclodextrin. In some embodiments, theprocesses described can be used to prepare a single batch of alkylatedcyclodextrin using greater than 300 kg, greater than 325 kg, greaterthan 350 kg, greater than 375 kg or greater than 400 kg of a startingcyclodextrin. In some embodiments, the amount of starting cyclodextrinis about 300 kg to about 400 kg, about 325 kg to about 375 kg, about 325kg to about 400 kg. In some embodiments, the amount of startingcyclodextrin is about 350 kg

Carbon Preparation Process

As discussed above, the purification of the crude alkylated cyclodextrindisclosed herein may utilize a carbon purification step to removeimpurities generated during the synthesis of the alkylated cyclodextrin.For example, such a purification process was disclosed in U.S. Pat. No.6,153,746, the contents of which are incorporated herein in theirentirety. Improvements to the carbon preparation process are describedin U.S. Pat. No. 7,635,773, where the activated carbon is washed until aconstant conductivity is reached prior to purification of the crudealkylated cyclodextrin. While the carbon preparation process describedin U.S. Pat. No. 7,635,773 removed some impurities, a high amount ofchloride in the alkylated cyclodextrin product remained. The chlorideimpurities may react with an active agent and cause degradation of theactive agent.

Further improvements to the carbon preparation process disclosed in U.S.Pat. No. 9,493,582, wherein the carbon preparation process includedwashing the carbon until a conductivity level of 10 μS/cm is reached.U.S. Pat. No. 10,040,872 discloses a method of preparing the carbon thatincludes a soaking step. While the methods described in theseapplications reduce the amount of chloride impurities in the finalalkylated cyclodextrin product, it is desirable to further reduce thechloride levels in the alkylated cyclodextrin product, in particularwhen the active agent is sensitive to chloride. The methods disclosedherein further reduce the chloride levels in the alkylated cyclodextrinproduct.

The conductivity of the activated carbon's water wash eluent can bedetermined using any method commonly used by one of skill in the art. Insome embodiments, the conductivity is measured using a conductivitymeter. In some embodiments, the conductivity is measured using ionchromatography.

In some embodiments, the conductivity of the activated carbon's waterwash eluent is measured before addition of alkylated cyclodextrinsolution that has been previously partially purified by diafiltration.In some embodiments, the conductivity of the activated carbon's waterwash eluent is measured after a water wash of the activated carbon. Insome embodiments, the conductivity of the activated carbon's water washeluent is measured after flowing water over the carbon. In someembodiments, the conductivity of the activated carbon's water washeluent prior to treating the partially purified alkylated cyclodextrinsolution with the activated carbon to produce a final purified alkylatedcyclodextrin composition is 35 μS/cm or less, 34 μS/cm or less, 33 μS/cmor less, 32 μS/cm or less, 31 μS/cm or less, 30 μS/cm or less, 29 μS/cmor less, 28 μS/cm or less, 27 μS/cm or less, 26 μS/cm or less, 25 μS/cmor less, 24 μS/cm, 23 μS/cm or less, 22 μS/cm or less, 21 μS/cm or less,20 μS/cm or less, 19 μS/cm or less, 18 μS/cm or less, 17 μS/cm or less,16 μS/cm or less, 15 μS/cm or less, 14 μS/cm or less, 13 μS/cm or less,12 μS/cm or less, 11 μS/cm or less, 10 μS/cm or less, 9 μS/cm or less, 8μS/cm or less, 7 μS/cm or less, 6 μS/cm or less, 5 μS/cm or less, 4μS/cm or less, 3 μS/cm or less, 2 μS/cm or less, or 1 μS/cm or less. Insome embodiments, the conductivity of the activated carbon's water washeluent prior to addition of the partially purified alkylatedcyclodextrin solution is 10 μS/cm to 15 μS/cm, 5 μS/cm to 15 μS/cm, 5μS/cm to 10 μS/cm, 4 μS/cm to 10 μS/cm, 3 μS/cm to 10 μS/cm, or 4 μS/cmto 8 μS/cm.

In some embodiments, the activated carbon is washed 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 times before treating the partiallypurified alkylated cyclodextrin solution with activated carbon. In someembodiments, the activated carbon is washed 1 or more, 2 or more, 3 ormore, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more,or 10 or more times before treating the partially purified alkylatedcyclodextrin solution with activated carbon.

Even when the activated carbon in the column is washed with water theremay be an inadequate wetting of the activated carbon. In the washprocedure there is no way to control for channeling through the carbonbed. It is believed that by more thoroughly washing the carbon beforecirculating the alkylated cyclodextrin solution it will reduce or removeall further addition of residual chloride from the alkylatedcyclodextrin composition product.

In some embodiments, the activated carbon is added to a dedicated tanksystem with an agitator and screen system. The activated carbon ischarged followed by a first carbon washing with several portions ofwater at a determined agitation rate for a determined time period.Following the water wash, the water layer is removed from the dedicatedtank and additional water washes occur. After additional water washesthe conductivity of the activated carbon is determined and when theconductivity is below a predetermined level the carbon is suspended inwater and the carbon/water slurry is pumped into a column for furthertreatment. The activated carbon would then be ready for flowing waterover the carbon or for further treatment comprising the step of adding aportion of the partially purified solution comprising the alkylatedcyclodextrin to the carbon, soaking the carbon in the partially purifiedsolution and eluting and discarding the solution. The predeterminedlevel of conductivity can be, for example, 35 μS/cm or less, 34 μS/cm orless, 33 μS/cm or less, 32 μS/cm or less, 31 μS/cm or less, 30 μS/cm orless, 29 μS/cm or less, 28 μS/cm or less, 27 μS/cm or less, 26 μS/cm orless, 25 μS/cm or less, 24 μS/cm, 23 μS/cm or less, 22 μS/cm or less, 21μS/cm or less, 20 μS/cm or less, 19 μS/cm or less, 18 μS/cm or less, 17μS/cm or less, 16 μS/cm or less, 15 μS/cm or less, 14 μS/cm or less, 13μS/cm or less, 12 μS/cm or less, 11 μS/cm or less, 10 μS/cm or less, 9μS/cm or less, 8 μS/cm or less, 7 μS/cm or less, 6 μS/cm or less, 5μS/cm or less, 4 μS/cm or less, 3 μS/cm or less, 2 μS/cm or less, or 1μS/cm or less. In some embodiments, the desired conductivity level maybe attained after about 6 to 12 hours of water washes.

The agitation can be measured in revolutions per minute (rpm). In someembodiments, the agitation rate can range, for example, from 5 rpm to300 rpm. For example, the agitation rate can be 5 rpm, 10 rpm, 20 rpm,30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, or 100 rpm. Theagitation time can range from 1 minute to 5 days. The agitation time canbe, for example, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24hours, 2 days, 3 days, or 4 days. In some embodiments, the agitationtime is 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 3 hours,5 minutes to 4 hours, 5 minutes to 5 hours, 10 minutes to 1 hour, 10minutes to 2 hours, 10 minutes to 3 hours, 10 minutes to 4 hours, 20minutes to 1 hour, 20 minutes to 2 hours, 20 minutes to 3 hours, 20minutes to 4 hours, 30 minutes to 1 hour, 30 minutes to 2 hours, 30minutes to 3 hours, or 30 minutes to 4 hours.

In some embodiments, the tank system is maintained at room temperature(25° C.) during the water washing process. In some embodiments, the tanksystem can be heated during the water washing process. In someembodiments, the temperature can range, for example, from 30° C. to 100°C. For example, the cooling temperature can be 30° C., 40° C., 50° C.,60° C., 70° C., 80° C., 90° C., or 100° C. The heating time can rangefrom 1 minute to 5 days. The heating time can be, for example, 5 minutesto 4 days, 5 minutes to 60 minutes, 10 minutes to 50 minutes, 20 minutesto 40 minutes, 30 minutes to 60 minutes, 2 hours to 24 hours, 3 hours to12 hours, 4 hours to 10 hours, 5 hours to 9 hours, 6 hours to 8 hours, 2days to 4 days, or 3 days to 4 days. In some embodiments, the heatingtime is 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 3 hours,5 minutes to 4 hours, 5 minutes to 5 hours, 10 minutes to 1 hour, 10minutes to 2 hours, 10 minutes to 3 hours, 10 minutes to 4 hours, 20minutes to 1 hour, 20 minutes to 2 hours, 20 minutes to 3 hours, 20minutes to 4 hours, 30 minutes to 1 hour, 30 minutes to 2 hours, 30minutes to 3 hours, or 30 minutes to 4 hours.

In some embodiments, the carbon transferred to the column may besubjected to a further washing process. The further washing process maycomprise flowing water over the activated carbon. In some embodiments,the column may be filled with purified water from top to bottom orbottom to top and held in the column for a period of time. In someembodiments the water is held in the column for at least thirty minutes.In some embodiments the water is held in the column for 30 to 45minutes. Purified water is then flowed over the activated carbon anddischarged. In some embodiments, the purified water is flowed in thesame direction that the water was filled in the first carbon washingprocess. In other embodiments, the water is flowed over the activatedcarbon in a different direction than the water was filled in the firstcarbon washing process. For example, in some embodiments, the water maybe filled in the first carbon washing process in a top to bottom and thewater may be flowed over the activated carbon in the second carbonwashing process in a top to bottom direction. In some embodiments, thewater may be filled in the first carbon washing process in a top tobottom direction and the water may be flowed over the activated carbonin the second carbon washing process in a bottom to top direction. Insome embodiments, the water may be filled in the first carbon washingprocess in a bottom to top direction and the water may be flowed overthe activated carbon in the second carbon washing process in a top tobottom direction.

Water may be flowed over the activated carbon for a set amount of time.For example, water can be flowed over the activated carbon for at least10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes,70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 270minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 420minutes, 450 minutes, 480 minutes, or more. For example, water may beflowed over the activated carbon for about 1 hour, about 2 hours, about3 hours, about 4 hours, or about 5 hours. The water may be flowed overthe activated carbon at a flow rate of at least 50 liters per hour, 100liters per hour, 150 liters per hour, 200 liters per hour, 250 litersper hour, 300 liters per hour, 350 liters per hour, 400 liters per hour,450 liters per hour, 500 liters per hour, or more. For example, watermay be flowed over the activated carbon for about 100 liters per hour,about 200 liters per hour, about 300 liters per hour, about 400 litersper hour, about 500 liters per hour, about 600 liters per hour, about700 liters per hour, about 800 liters per hour, about 900 liters perhour, or about 1,000 liters per hour. After flowing water over thecarbon, the columns may then be flushed with purified water from the topof the column for 30 minutes and then drained from the column.

In some embodiments, the activated carbon subjected to a further carbonwashing process comprising adding a portion of the partially purifiedalkylated cyclodextrin solution to the activated carbon, soaking theactivated carbon in the partially purified alkylated cyclodextrinsolution, and eluting and discarding the partially purified alkylatedcyclodextrin solution. The alkylated cyclodextrin solution may be filledin a top to bottom direction or a bottom to top direction. In anembodiment, the activated carbon is allowed to soak for a set amount oftime before the partially purified alkylated cyclodextrin solution iseluted. For example, the activated carbon can soak for at least 10minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes,150 minutes, 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300minutes, 330 minutes, 360 minutes, 390 minutes, 420 minutes, 450minutes, 480 minutes, or more. In one embodiment, the activated carbonis allowed to soak for at least 120 minutes.

In some embodiments, the carbon may be agitated during the soakingprocess at a rate between, for example, from 5 rpm to 300 rpm. Forexample, the agitation rate can be 5 rpm, 10 rpm, 20 rpm, 30 rpm, 40rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, or 100 rpm. In someembodiments, the agitation rate may be bout 40-50 rpm.

In some embodiments, the temperature can range for the soaking of thecarbon in the alkylated cyclodextrin solution, from 5° C. to 100° C. Forexample, the soaking temperature can be 10° C., 20° C., 25° C., 30° C.,40° C., 50° C., 60° C., 70° C., 80° C., 90° C., or 100° C. In someembodiments, the soaking temperature is room temperature.

In some embodiments, the activated carbon may subjected to yet a furthercarbon washing process after the soaking process. This further washingprocess comprises filling the column with purified water and letting thewater sit for a period of time. In some embodiments, the water is addedin a top to bottom direction. In other embodiments, the water is addedin a bottom to top direction. In some embodiments, the water may beallowed to sit for about 30 minutes. The purified water is then drainedfrom the bottom of the column. This process may be continued for atleast one hour and the conductivity of the activated carbon isdetermined. When the conductivity is below a desired predeterminedlevel, the column may be charged with water and used in the purificationof the alkylated cyclodextrin. If the conductivity is above a desiredpredetermined level, this further washing process may be repeated. Thepredetermined level of conductivity can be, for example, 35 μS/cm orless, 34 μS/cm or less, 33 μS/cm or less, 32 μS/cm or less, 31 μS/cm orless, 30 μS/cm or less, 29 μS/cm or less, 28 μS/cm or less, 27 μS/cm orless, 26 μS/cm or less, 25 μS/cm or less, 24 μS/cm, 23 μS/cm or less, 22μS/cm or less, 21 μS/cm or less, 20 μS/cm or less, 19 μS/cm or less, 18μS/cm or less, 17 μS/cm or less, 16 μS/cm or less, 15 μS/cm or less, 14μS/cm or less, 13 μS/cm or less, 12 μS/cm or less, 11 μS/cm or less, 10μS/cm or less, 9 μS/cm or less, 8 μS/cm or less, 7 μS/cm or less, 6μS/cm or less, 5 μS/cm or less, 4 μS/cm or less, 3 μS/cm or less, 2μS/cm or less, or 1 μS/cm or less. In some embodiments, thepredetermined level of conductivity is 10 μS/cm or less.

Uses of Alkylated Cyclodextrin Compositions

Among other uses, an alkylated cyclodextrin of the present disclosurecan be used to solubilize and/or stabilize a variety of differentmaterials and to prepare formulations for particular applications. Thealkylated cyclodextrin described herein can provide enhanced solubilityand/or enhanced chemical, thermochemical, hydrolytic and/orphotochemical stability of other ingredients in a composition. Forexample, an alkylated cyclodextrin can be used to stabilize an activeagent in an aqueous medium. An alkylated cyclodextrin can also be usedto increase the solubility of an active agent in an aqueous medium.

The alkylated cyclodextrin composition of the present disclosureincludes one or more active agents. The one or more active agentsincluded in the composition of the present disclosure can possess a widerange of water solubility, bioavailability and hydrophilicity. Activeagents to which the present disclosure is particularly suitable includewater insoluble, poorly water-soluble, slightly water-soluble,moderately water-soluble, water-soluble, very water-soluble,hydrophobic, and/or hydrophilic therapeutic agents. It will beunderstood by a person of ordinary skill in the art one or more activeagents present in a composition of the present disclosure isindependently selected at each occurrence from any known active agentand from those disclosed herein. It is not necessary that the one ormore active agents form a complex with the alkylated cyclodextrin, orform an ionic association with the alkylated cyclodextrin.

Active agents generally include physiologically or pharmacologicallyactive substances that produce a systemic or localized effect or effectson animals and human beings. Active agents also include pesticides,herbicides, insecticides, antioxidants, plant growth instigators,sterilization agents, catalysts, chemical reagents, food products,nutrients, cosmetics, vitamins, sterility inhibitors, fertilityinstigators, microorganisms, flavoring agents, sweeteners, cleansingagents, pharmaceutically effective active agents, and other suchcompounds for pharmaceutical, veterinary, horticultural, household,food, culinary, agricultural, cosmetic, industrial, cleaning,confectionery and flavoring applications. The active agent can bepresent in its neutral, ionic, salt, basic, acidic, natural, synthetic,diastereomeric, isomeric, enantiomerically pure, racemic, hydrate,chelate, derivative, analog, or other common form.

Representative pharmaceutically effective active agents includenutrients and nutritional agents, hematological agents, endocrine andmetabolic agents, cardiovascular agents, renal and genitourinary agents,respiratory agents, central nervous system agents, gastrointestinalagents, anti-fungal agents, anti-infective agents, biologic andimmunological agents, dermatological agents, ophthalmic agents,antineoplastic agents, and diagnostic agents. Exemplary nutrients andnutritional agents include as minerals, trace elements, amino acids,lipotropic agents, enzymes and chelating agents. Exemplary hematologicalagents include hematopoietic agents, antiplatelet agents,anticoagulants, coumarin and indandione derivatives, coagulants,thrombolytic agents, antisickling agents, hemorrheologic agents,antihemophilic agents, hemostatics, plasma expanders and hemin.Exemplary endocrine and metabolic agents include sex hormones,uterine-active agents, bisphosphonates, antidiabetic agents, glucoseelevating agents, corticosteroids, adrenocortical steroids, parathyroidhormone, thyroid drugs, growth hormones, posterior pituitary hormones,octreotide acetate, imiglucerase, calcitonin-salmon, sodiumphenylbutyrate, betaine anhydrous, cysteamine bitartrate, sodiumbenzoate and sodium phenylacetate, bromocriptine mesylate, cabergoline,agents for gout, and antidotes. Antifungal agents suitable for use withthe alkylated cyclodextrin composition of the present disclosureinclude, but are not limited to, posaconazole, voriconazole,clotrimazole, ketoconazole, oxiconazole, sertaconazole, tetconazole,fluconazole, itraconazole and miconazole. Antipsychotic agents suitablefor use with the alkylated cyclodextrin composition of the presentdisclosure include, but are not limited to, clozapine, prochlorperazine,haloperidol, thioridazine, thiothixene, risperidone, trifluoperazinehydrochloride, chlorpromazine, aripiprazole, loxapine, loxitane,olanzapine, quetiapine fumarate, risperidone and ziprasidone.

Exemplary cardiovascular agents include nootropic agents, antiarrhythmicagents, calcium channel blocking agents, vasodilators,antiadrenergics/sympatholytics, renin angiotensin system antagonists,antihypertensive agent combinations, agents for pheochromocytoma, agentsfor hypertensive emergencies, antihyperlipidemic agents,antihyperlipidemic combination products, vasopressors used in shock,potassium removing resins, edetate disodium, cardioplegic solutions,agents for patent ductus arteriosus, and sclerosing agents. Exemplaryrenal and genitourinary agents include interstitial cystitis agents,cellulose sodium phosphate, anti-impotence agents, acetohydroxamic acid(aha), genitourinary irrigants, cystine-depleting agents, urinaryalkalinizers, urinary acidifiers, anticholinergics, urinarycholinergics, polymeric phosphate binders, vaginal preparations, anddiuretics. Exemplary respiratory agents include bronchodilators,leukotriene receptor antagonists, leukotriene formation inhibitors,respiratory inhalant products, nasal decongestants, respiratory enzymes,lung surfactants, antihistamines, nonnarcotic antitussives, andexpectorants. Exemplary central nervous system agents include CNSstimulants, narcotic agonist analgesics, narcotic agonist-antagonistanalgesics, central analgesics, acetaminophen, salicylates, nonnarcoticanalgesics, nonsteroidal anti-inflammatory agents, agents for migraine,antiemetic/antivertigo agents, antianxiety agents, antidepressants,antipsychotic agents, cholinesterase inhibitors, nonbarbituratesedatives and hypnotics, nonprescription sleep aids, barbituratesedatives and hypnotics, general anesthetics, injectable localanesthetics, anticonvulsants, muscle relaxants, antiparkinson agents,adenosine phosphate, cholinergic muscle stimulants, disulfuram, smokingdeterrents, riluzole, hyaluronic acid derivatives, and botulinum toxins.Exemplary gastrointestinal agents including H. pylori agents, histamineH2 antagonists, proton pump inhibitors, sucralfate, prostaglandins,antacids, gastrointestinal anticholinergics/antispasmodics, mesalamine,olsalazine sodium, balsalazide disodium, sulfasalazine, celecoxib,infliximab, tegaserod maleate, laxatives, antidiarrheals,antiflatulents, lipase inhibitors, GI stimulants, digestive enzymes,gastric acidifiers, hydrocholeretics, gallstone solubilizing agents,mouth and throat products, systemic deodorizers, and anorectalpreparations. Exemplary anti-infective agents including penicillins,cephalosporins and related antibiotics, carbapenem, monobactams,chloramphenicol, quinolones, fluoroquinolones, tetracyclines,macrolides, spectinomycin, streptogramins, vancomycin, oxalodinones,lincosamides, oral and parenteral aminoglycosides, colistimethatesodium, polymyxin b sulfate, bacitracin, metronidazole, sulfonamides,nitrofurans, methenamines, folate antagonists, antifungal agents,antimalarial preparations, antituberculosis agents, amebicides,antiviral agents, antiretroviral agents, leprostatics, antiprotozoals,anthelmintics, and cdc anti-infective agents. Exemplary biologic andimmunological agents including immune globulins, monoclonal antibodyagents, antivenins, agents for active immunization, allergenic extracts,immunologic agents, and antirheumatic agents. Exemplary dermatologicalagents include topical antihistamine preparations, topicalanti-infectives, anti-inflammatory agents, anti-psoriatic agents,antiseborrheic products, arnica, astringents, cleansers, capsaicin,destructive agents, drying agents, enzyme preparations, topicalimmunomodulators, keratolytic agents, liver derivative complex, topicallocal anesthetics, minoxidil, eflornithine hydrochloride,photochemotherapy agents, pigment agents, topical poison ivy products,topical pyrimidine antagonist, pyrithione zinc, retinoids, rexinoids,scabicides/pediculicides, wound healing agents, emollients, protectants,sunscreens, ointment and lotion bases, rubs and liniments, dressings andgranules, and physiological irrigating solutions. Exemplary ophthalmicagents include agents for glaucoma, mast cell stabilizers, ophthalmicantiseptics, ophthalmic phototherapy agents, ocular lubricants,artificial tears, ophthalmic hyperosmolar preparations, and contact lensproducts. Exemplary antineoplastic agents include alkylating agents,antimetabolites, antimitotic agents, epipodophyllotoxins, antibiotics,hormones, enzymes, radiopharmaceuticals, platinum coordination complex,anthracenedione, substituted ureas, methylhydrazine derivatives,imidazotetrazine derivatives, cytoprotective agents, DNA topoisomeraseinhibitors, biological response modifiers, retinoids, rexinoids,monoclonal antibodies, protein-tyrosine kinase inhibitors, porfimersodium, mitotane (o, p′-ddd), and arsenic trioxide. Exemplary diagnosticagents include in vivo diagnostic aids, in vivo diagnostic biologicals,and radiopaque agents.

Exemplary active agents also include compounds that are sensitive tochloride levels. Exemplary chloride sensitive active agents includeproteasome inhibitors such as bortezomib, disulfiram,epigallocatchin-3-gallate, salinosporamide A, and carfilzomib.

The above-listed active agents should not be considered exhaustive andis merely exemplary of the many embodiments considered within the scopeof the disclosure. Many other active agents can be administered with theformulation of the present disclosure.

A formulation of the disclosure can be used to deliver two or moredifferent active agents. Particular combinations of active agents can beprovided in a formulation of the disclosure. Some combinations of activeagents include: 1) a first drug from a first therapeutic class and adifferent second drug from the same therapeutic class; 2) a first drugfrom a first therapeutic class and a different second drug from adifferent therapeutic class; 3) a first drug having a first type ofbiological activity and a different second drug having about the samebiological activity; and 4) a first drug having a first type ofbiological activity and a different second drug having a differentsecond type of biological activity. Exemplary combinations of activeagents are described herein.

An active agent contained within a formulation of the disclosure can bepresent as its pharmaceutically acceptable salt. As used herein,“pharmaceutically acceptable salt” refers to derivatives of thedisclosed compounds wherein the active agent is modified by reacting itwith an acid and/or base as needed to form an ionically bound pair.Examples of pharmaceutically acceptable salts include conventionalnon-toxic salts or the quaternary ammonium salts of a compound formed,for example, from non-toxic inorganic or organic acids. Suitablenon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric,nitric and others known to those of ordinary skill in the art. The saltsprepared from organic acids such as amino acids, acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and others knownto those of ordinary skill in the art. Pharmaceutically acceptable saltssuitable for use with the present disclosure can be prepared using anactive agent that includes a basic or acidic group by conventionalchemical methods. Suitable addition salts are found in Remington'sPharmaceutical Sciences (17th ed., Mack Publishing Co., Easton, P A,1985), the relevant disclosure of which is hereby incorporated byreference in its entirety.

The present disclosure is also directed to a method for stabilizing anactive agent, the method comprising providing an alkylated cyclodextrincomposition comprising an alkylated cyclodextrin described herein; andcombining the alkylated cyclodextrin composition with an active agent.

The method of stabilizing an active agent can be performed wherein thecomposition comprising one or more active agents and an alkylatedcyclodextrin composition comprising an alkylated cyclodextrin is presentas a dry solution, a wet solution, an inhalable composition, aparenteral composition, a solid solution, a solid mixture, a granulate,a gel, and other active agent compositions known to persons of ordinaryskill in the art.

In some embodiments, the method of stabilizing an active agent providesan active agent assay of 98% or more, 98.5% or more, 99% or more, or99.5% or more of the active agent after the composition comprising oneor more active agents and an alkylated cyclodextrin composition ismaintained at a temperature of 80° C. for a period of 120 minutes.

In some embodiments, the method of stabilizing provides an alkylatedcyclodextrin composition comprising an alkylated cyclodextrin with aphosphate level of less than 400 ppm, less than 300 ppm, less than 200ppm, less than 125 ppm, less than 100 ppm, less than 75 ppm, or lessthan 50 ppm.

In some embodiments, the method of stabilizing provides an alkylatedcyclodextrin composition comprising an alkylated cyclodextrin whereinthe alkylated cyclodextrin composition has an absorption of 0.5 A.U. orless, as determined by UV/vis spectrophotometry at a wavelength of 245nm to 270 nm for an aqueous solution containing 300 mg of the alkylatedcyclodextrin composition per mL of solution in a cell having a 1 cm pathlength. In some embodiments, said absorption of 0.5 A.U. or less is dueto a drug degrading agent.

Generally, the alkylated cyclodextrin is present in an amount sufficientto stabilize the active agent. An amount sufficient can be a molar ratioof 0.1:1 to 10:1, 0.5:1 to 10:1, 0.8:1 to 10:1, or 1:1 to 5:1 (alkylatedcyclodextrin:active agent).

A cyclodextrin in the combination composition need not bind with anothermaterial, such as an active agent, present in a formulation containingit. However, if a cyclodextrin binds with another material, such a bondcan be formed as a result of an inclusion complexation, an ion pairformation, a hydrogen bond, and/or a Van der Waals interaction.

An anionic derivatized cyclodextrin can complex or otherwise bind withan acid-ionizable agent. As used herein, the term acid-ionizable agentis taken to mean any compound that becomes or is ionized in the presenceof an acid. An acid-ionizable agent comprises at least oneacid-ionizable functional group that becomes ionized when exposed toacid or when placed in an acidic medium. Exemplary acid-ionizablefunctional groups include a primary amine, secondary amine, tertiaryamine, quaternary amine, aromatic amine, unsaturated amine, primarythiol, secondary thiol, sulfonium, hydroxyl, enol and others known tothose of ordinary skill in the chemical arts.

The degree to which an acid-ionizable agent is bound by non-covalentionic binding versus inclusion complexation formation can be determinedspectrometrically using methods such as ¹H-NMR, ¹³C-NMR, or circulardichroism, for example, and by analysis of the phase solubility data forthe acid-ionizable agent and anionic derivatized cyclodextrin. Theartisan of ordinary skill in the art will be able to use theseconventional methods to approximate the amount of each type of bindingthat is occurring in solution to determine whether or not bindingbetween the species is occurring predominantly by non-covalent ionicbinding or inclusion complex formation. Under conditions wherenon-covalent ionic bonding predominates over inclusion complexformation, the amount of inclusion complex formation, measured by NMR orcircular dichroism, will be reduced even though the phase solubilitydata indicates significant binding between the species under thoseconditions; moreover, the intrinsic solubility of the acid-ionizableagent, as determined from the phase solubility data, will generally behigher than expected under those conditions.

As used herein, the term “non-covalent ionic bond” refers to a bondformed between an anionic species and a cationic species. A bond isnon-covalent such that the two species together form a salt or ion pair.An anionic derivatized cyclodextrin provides the anionic species of theion pair and the acid-ionizable agent provides the cationic species ofthe ion pair. Since an anionic derivatized cyclodextrin is multi-valent,an alkylated cyclodextrin can form an ion pair with one or moreacid-ionizable or otherwise cationic agents.

A liquid formulation of the disclosure can be converted to a solidformulation for reconstitution. A reconstitutable solid compositionaccording to the disclosure comprises an active agent, a derivatizedcyclodextrin and optionally at least one other pharmaceutical excipient.A reconstitutable composition can be reconstituted with an aqueousliquid to form a liquid formulation that is preserved. The compositioncan comprise an admixture (minimal to no presence of an inclusioncomplex) of a solid derivatized cyclodextrin and an activeagent-containing solid and optionally at least one solid pharmaceuticalexcipient, such that a major portion of the active agent is notcomplexed with the derivatized cyclodextrin prior to reconstitution.Alternatively, the composition can comprise a solid mixture of aderivatized cyclodextrin and an active agent, wherein a major portion ofthe active agent is complexed with the derivatized cyclodextrin prior toreconstitution. A reconstitutable solid composition can also comprise aderivatized cyclodextrin and an active agent where substantially all orat least a major portion of the active agent is complexed with thederivatized cyclodextrin.

A reconstitutable solid composition can be prepared according to any ofthe following processes. A liquid formulation of the disclosure is firstprepared, then a solid is formed by lyophilization (freeze-drying),spray-drying, spray freeze-drying, antisolvent precipitation, asepticspray drying, various processes utilizing supercritical or nearsupercritical fluids, or other methods known to those of ordinary skillin the art to make a solid for reconstitution.

A liquid vehicle included in a formulation of the disclosure cancomprise an aqueous liquid carrier (e.g., water), an aqueous alcohol, anaqueous organic solvent, a non-aqueous liquid carrier, and combinationsthereof.

The formulation of the present disclosure can include one or morepharmaceutical excipients such as a conventional preservative,antifoaming agent, antioxidant, buffering agent, acidifying agent,alkalizing agent, bulking agent, colorant, complexation-enhancing agent,cryoprotectant, electrolyte, glucose, emulsifying agent, oil,plasticizer, solubility-enhancing agent, stabilizer, tonicity modifier,flavors, sweeteners, adsorbents, antiadherent, binder, diluent, directcompression excipient, disintegrant, glidant, lubricant, opaquant,polishing agent, complexing agents, fragrances, other excipients knownby those of ordinary skill in the art for use in formulations,combinations thereof.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suchcompounds include, by way of example and without limitation, ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organicamine base, alkaline amino acids and trolamine and others known to thoseof ordinary skill in the art.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium for product stability. Suchcompounds include, by way of example and without limitation, aceticacid, acidic amino acids, citric acid, fumaric acid and other α-hydroxyacids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid,tartaric acid and nitric acid and others known to those of ordinaryskill in the art.

As used herein, the term “antiadherent” is intended to mean an agentthat prevents the sticking of solid dosage formulation ingredients topunches and dies in a tableting machine during production. Suchcompounds include, by way of example and without limitation, magnesiumstearate, talc, calcium stearate, glyceryl behenate, polyethyleneglycol, hydrogenated vegetable oil, mineral oil, stearic acid and othermaterials known to one of ordinary skill in the art.

As used herein, the term “binder” is intended to mean a substance usedto cause adhesion of powder particles in solid dosage formulations. Suchcompounds include, by way of example and without limitation, acacia,alginic acid, carboxymethylcellulose sodium, poly(vinylpyrrolidone), acompressible sugar, ethylcellulose, gelatin, liquid glucose,methylcellulose, povidone and pregelatinized starch and other materialsknown to one of ordinary skill in the art.

When needed, binders can also be included in the dosage forms. Exemplarybinders include acacia, tragacanth, gelatin, starch, cellulose materialssuch as methyl cellulose and sodium carboxymethylcellulose, alginicacids and salts thereof, polyethylene glycol, guar gum, polysaccharide,bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™F127), collagen, albumin, gelatin, cellulosics in non-aqueous solvents,combinations thereof and others known to those of ordinary skill in theart. Other binders include, for example, polypropylene glycol,polyoxyethylene-polypropylene copolymer, polyethylene ester,polyethylene sorbitan ester, polyethylene oxide, combinations thereofand other materials known to one of ordinary skill in the art.

As used herein, a conventional preservative is a compound used to atleast reduce the rate at which bioburden increases, but maintainsbioburden steady or reduces bioburden after contamination. Suchcompounds include, by way of example and without limitation,benzalkonium chloride, benzethonium chloride, benzoic acid, benzylalcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethylalcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal,metacresol, myristylgamma picolinium chloride, potassium benzoate,potassium sorbate, sodium benzoate, sodium propionate, sorbic acid,thymol, and methyl, ethyl, propyl or butyl parabens and others known tothose of ordinary skill in the art. It is understood that somepreservatives can interact with the alkylated cyclodextrin thus reducingthe preservative effectiveness. Nevertheless, by adjusting the choice ofpreservative and the concentrations of preservative and the alkylatedcyclodextrin adequately preserved formulations can be found.

As used herein, the term “diluent” or “filler” is intended to mean aninert substance used as a filler to create the desired bulk, flowproperties, and compression characteristics in the preparation of aliquid or solid dosage form. Such compounds include, by way of exampleand without limitation, a liquid vehicle (e.g., water, alcohol,solvents, and the like), dibasic calcium phosphate, kaolin, lactose,dextrose, magnesium carbonate, sucrose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sorbitol,and starch and other materials known to one of ordinary skill in theart.

As used herein, the term “direct compression excipient” is intended tomean a compound used in compressed solid dosage forms. Such compoundsinclude, by way of example and without limitation, dibasic calciumphosphate, and other materials known to one of ordinary skill in theart.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, acetone, potassium metabisulfite,potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid,butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid,monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate,sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehydesulfoxylate, thioglycolic acid, EDTA, pentetate, and sodiummetabisulfite and others known to those of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, acetic acid, sodium acetate, adipic acid, benzoic acid,sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleicacid, monobasic sodium phosphate, dibasic sodium phosphate,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, lactic acid,tartaric acid, potassium metaphosphate, potassium phosphate, monobasicsodium acetate, sodium bicarbonate, tris, sodium tartrate and sodiumcitrate anhydrous and dihydrate and others known to those of ordinaryskill in the art.

A complexation-enhancing agent can be added to a formulation of thedisclosure. When such an agent is present, the ratio ofcyclodextrin/active agent can be changed. A complexation-enhancing agentis a compound, or compounds, that enhance(s) the complexation of theactive agent with the cyclodextrin. Suitable complexation enhancingagents include one or more pharmacologically inert water-solublepolymers, hydroxy acids, and other organic compounds typically used inpreserved formulations to enhance the complexation of a particular agentwith cyclodextrins.

Hydrophilic polymers can be used as complexation-enhancing,solubility-enhancing and/or water activity reducing agents to improvethe performance of formulations containing a CD-based preservative.Loftsson has disclosed a number of polymers suitable for combined usewith a cyclodextrin (underivatized or derivatized) to enhance theperformance and/or properties of the cyclodextrin. Suitable polymers aredisclosed in Pharmazie 56:746 (2001); Int. J. Pharm. 212:29 (2001);Cyclodextrin: From Basic Research to Market, 10th Int'l CyclodextrinSymposium, Ann Arbor, MI, US, May 21-24, p. 10-15 (2000); PCT Int'l Pub.No. WO 99/42111; Pharmazie 53:733 (1998); Pharm. Technol. Eur. 9:26(1997); J. Pharm. Sci. 85:1017 (1996); European Patent Appl. No. 0 579435; Proc. of the 9th Int'l Symposium on Cyclodextrins, Santiago deComostela, ES, May 31-Jun. 3, 1998, pp. 261-264 (1999); S.T.P. PharmaSciences 9:237 (1999); Amer. Chem. Soc. Symposium Series 737(Polysaccharide Applications):24-45 (1999); Pharma. Res. 15:1696 (1998);Drug Dev. Ind. Pharm. 24:365 (1998); Int. J. Pharm. 163:115 (1998); Bookof Abstracts, 216th Amer. Chem. Soc. Nat'l Meeting, Boston, August 23-27CELL-016 (1998); J. Controlled Release 44:95 (1997); Pharm. Res. (1997)14(11), S203; Invest. Ophthalmol. Vis. Sci. 37:1199 (1996); Proc. of the23rd Int'l Symposium on Controlled Release of Bioactive Materials453-454 (1996); Drug Dev. Ind. Pharm. 22:401 (1996); Proc. of the 8thInt'l Symposium on Cyclodextrins, Budapest, HU, Mar. 31-Apr. 2, 1996,pp. 373-376 (1996); Pharma. Sci. 2:277 (1996); Eur. J. Pharm. Sci.4S:S144 (1996); 3rd Eur. Congress of Pharma. Sci. Edinburgh, Scotland,UK Sep. 15-17, 1996; Pharmazie 51:39 (1996); Eur. J. Pharm. Sci. 4S:S143(1996); U.S. Pat. Nos. 5,472,954 and 5,324,718; Int. J. Pharm. 126:73(1995); Abstracts of Papers of the Amer. Chem. Soc. 209:33-CELL (1995);Eur. J. Pharm. Sci. 2:297 (1994); Pharm. Res. 11:S225 (1994); Int. J.Pharm. 104:181 (1994); and Int. J. Pharm. 110:169 (1994), the entiredisclosures of which are hereby incorporated by reference in theirentirety.

Other suitable polymers are well-known excipients commonly used in thefield of pharmaceutical formulations and are included in, for example,Remington's Pharmaceutical Sciences, 18th ed., pp. 291-294, A.R. Gennaro(editor), Mack Publishing Co., Easton, P A (1990); A. Martin et al.,Physical Pharmacy. Physical Chemical Principles in PharmaceuticalSciences, 3d ed., pp. 592-638 (Lea & Febinger, Philadelphia, P A (1983);A. T. Florence et al., Physicochemical Principles of Pharmacy, 2d ed.,pp. 281-334, MacMillan Press, London, UK (1988), the disclosures ofwhich are incorporated herein by reference in their entirety. Stillother suitable polymers include water-soluble natural polymers,water-soluble semi-synthetic polymers (such as the water-solublederivatives of cellulose) and water-soluble synthetic polymers. Thenatural polymers include polysaccharides such as inulin, pectin, alginderivatives (e.g. sodium alginate) and agar, and polypeptides such ascasein and gelatin. The semi-synthetic polymers include cellulosederivatives such as methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, their mixed ethers such ashydroxypropylmethylcellulose and other mixed ethers such ashydroxyethyl-ethylcellulose and hydroxypropylethylcellulose,hydroxypropylmethylcellulose phthalate and carboxymethylcellulose andits salts, especially sodium carboxymethylcellulose. The syntheticpolymers include polyoxyethylene derivatives (polyethylene glycols) andpolyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone andpolystyrene sulfonate) and various copolymers of acrylic acid (e.g.carbomer). Other natural, semi-synthetic and synthetic polymers notnamed here which meet the criteria of water solubility, pharmaceuticalacceptability and pharmacological inactivity are likewise considered tobe within the ambit of the present disclosure.

As used herein, a fragrance is a relatively volatile substance orcombination of substances that produces a detectable aroma, odor orscent. Exemplary fragrances include those generally accepted as safe bythe U.S. Food and Drug Administration.

As used herein, the term “glidant” is intended to mean an agent used insolid dosage formulations to promote flowability of the solid mass. Suchcompounds include, by way of example and without limitation, colloidalsilica, cornstarch, talc, calcium silicate, magnesium silicate,colloidal silicon, tribasic calcium phosphate, silicon hydrogel andother materials known to one of ordinary skill in the art.

As used herein, the term “lubricant” is intended to mean a substanceused in solid dosage formulations to reduce friction during compression.Such compounds include, by way of example and without limitation,calcium stearate, magnesium stearate, polyethylene glycol, talc, mineraloil, stearic acid, and zinc stearate and other materials known to one ofordinary skill in the art.

As used herein, the term “opaquant” is intended to mean a compound usedto render a coating opaque. An opaquant can be used alone or incombination with a colorant. Such compounds include, by way of exampleand without limitation, titanium dioxide, talc and other materials knownto one of ordinary skill in the art.

As used herein, the term “polishing agent” is intended to mean acompound used to impart an attractive sheen to solid dosage forms. Suchcompounds include, by way of example and without limitation, carnaubawax, white wax and other materials known to one of ordinary skill in theart.

As used herein, the term “disintegrant” is intended to mean a compoundused in solid dosage forms to promote the disruption of the solid massinto smaller particles which are more readily dispersed or dissolved.Exemplary disintegrants include, by way of example and withoutlimitation, starches such as corn starch, potato starch, pre-gelatinizedand modified starches thereof, sweeteners, clays, bentonite,microcrystalline cellulose (e.g., AVICEL®), carboxymethylcellulosecalcium, croscarmellose sodium, alginic acid, sodium alginate, cellulosepolacrilin potassium (e.g., Amberlite®), alginates, sodium starchglycolate, gums, agar, guar, locust bean, karaya, pectin, tragacanth,crospovidone and other materials known to one of ordinary skill in theart.

As used herein, the term “stabilizer” is intended to mean a compoundused to stabilize the therapeutic agent against physical, chemical, orbiochemical process which would reduce the therapeutic activity of theagent. Suitable stabilizers include, by way of example and withoutlimitation, albumin, sialic acid, creatinine, glycine and other aminoacids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose,glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols,sodium caprylate and sodium saccharin and other known to those ofordinary skill in the art.

As used herein, the term “tonicity modifier” is intended to mean acompound or compounds that can be used to adjust the tonicity of theliquid formulation. Suitable tonicity modifiers include glycerin,lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol,trehalose and others known to those of ordinary skill in the art. Insome embodiments, the tonicity of the liquid formulation approximatesthe tonicity of blood or plasma.

As used herein, the term “antifoaming agent” is intended to mean acompound or compounds that prevents or reduces the amount of foamingthat forms on the surface of the liquid formulation. Suitableantifoaming agents include dimethicone, simethicone, octoxynol andothers known to those of ordinary skill in the art.

As used herein, the term “bulking agent” is intended to mean a compoundused to add bulk to the solid product and/or assist in the control ofthe properties of the formulation during lyophilization. Such compoundsinclude, by way of example and without limitation, dextran, trehalose,sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol,dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and othersknown to those of ordinary skill in the art.

As used herein, the term “cryoprotectant” is intended to mean a compoundused to protect an active therapeutic agent from physical or chemicaldegradation during lyophilization. Such compounds include, by way ofexample and without limitation, dimethyl sulfoxide, glycerol, trehalose,propylene glycol, polyethylene glycol, and others known to those ofordinary skill in the art.

As used herein, the term “emulsifier” or “emulsifying agent” is intendedto mean a compound added to one or more of the phase components of anemulsion for the purpose of stabilizing the droplets of the internalphase within the external phase. Such compounds include, by way ofexample and without limitation, lecithin,polyoxylethylene-polyoxypropylene ethers, polyoxylethylene-sorbitanmonolaurate, polysorbates, sorbitan esters, stearyl alcohol, tyloxapol,tragacanth, xanthan gum, acacia, agar, alginic acid, sodium alginate,bentonite, carbomer, sodium carboxymethylcellulose, cholesterol,gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, octoxynol,oleyl alcohol, polyvinyl alcohol, povidone, propylene glycolmonostearate, sodium lauryl sulfate, and others known to those ofordinary skill in the art.

A solubility-enhancing agent can be added to the formulation of thepresent disclosure. A solubility-enhancing agent is a compound, orcompounds, that enhance(s) the solubility of the active agent when in aliquid formulation. When such an agent is present, the ratio ofcyclodextrin/active agent can be changed. Suitable solubility enhancingagents include one or more organic solvents, detergents, soaps,surfactant and other organic compounds typically used in parenteralformulations to enhance the solubility of a particular agent.

Suitable organic solvents include, for example, ethanol, glycerin,polyethylene glycols, propylene glycol, poloxomers, and others known tothose of ordinary skill in the art.

Formulations comprising the alkylated cyclodextrin of the presentdisclosure can include oils (e.g., fixed oils, peanut oil, sesame oil,cottonseed oil, corn oil olive oil, and the like), fatty acids (e.g.,oleic acid, stearic acid, isostearic acid, and the like), fatty acidesters (e.g., ethyl oleate, isopropyl myristate, and the like), fattyacid glycerides, acetylated fatty acid glycerides, and combinationsthereof. Formulations comprising the alkylated cyclodextrin of thepresent disclosure can also include alcohols (e.g., ethanol,iso-propanol, hexadecyl alcohol, glycerol, propylene glycol, and thelike), glycerol ketals (e.g., 2,2-dimethyl-1,3-dioxolane-4-methanol, andthe like), ethers (e.g., poly(ethylene glycol) 450, and the like),petroleum hydrocarbons (e.g., mineral oil, petrolatum, and the like),water, surfactants, suspending agents, emulsifying agents, andcombinations thereof.

It should be understood, that compounds used in the art ofpharmaceutical formulations generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

Formulations comprising the alkylated cyclodextrin of the presentdisclosure can also include biological salt(s), sodium chloride,potassium chloride, and other electrolyte(s).

Since some active agents are subject to oxidative degradation, a liquidformulation according to the disclosure can be substantiallyoxygen-free. For example, the headspace of a container containing aliquid formulation can made oxygen-free, substantially oxygen-free, oroxygen-reduced by purging the headspace with an inert gas (e.g.,nitrogen, argon, carbon dioxide, and the like), or by bubbling an inertgas through a liquid formulation. For long-term storage, a liquidformulation containing an active agent subject to oxidative degradationcan be stored in an oxygen-free or oxygen-reduced environment. Removalof oxygen from the formulation will enhance preservation of theformulation against aerobic microbes; whereas, addition of oxygen to theformulation will enhance preservation against anaerobic microbes.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “patient” or “subject” are taken to mean warmblooded animals such as mammals, for example, cats, dogs, mice, guineapigs, horses, bovine cows, sheep, non-humans, and humans.

A formulation of the disclosure will comprise an active agent present inan effective amount. By the term “effective amount,” is meant the amountor quantity of active agent that is sufficient to elicit the required ordesired response, or in other words, the amount that is sufficient toelicit an appreciable biological response when administered to asubject.

The compositions of the present disclosure can be present informulations for dosage forms such as a reconstitutable solid, tablet,capsule, pill, troche, patch, osmotic device, stick, suppository,implant, gum, effervescent composition, injectable liquid, ophthalmic ornasal solutions, or inhalable powders or solutions.

The disclosure also provides methods of preparing a liquid formulationcomprising one or more active agents and an alkylated cyclodextrin,wherein the alkylated cyclodextrin comprises an alkylated cyclodextrin.A first method comprises: forming a first aqueous solution comprising analkylated cyclodextrin composition; forming a second solution orsuspension comprising one or more active agents; and mixing the firstand second solutions to form a liquid formulation. A similar secondmethod comprises adding one or more active agents directly to a firstsolution without formation of the second solution. A third methodcomprises adding an alkylated cyclodextrin directly to asolution/suspension containing one or more active agents. A fourthmethod comprises adding a solution comprising one or more active agentsto a powdered or particulate alkylated cyclodextrin composition. A fifthmethod comprises adding one or more active agents directly to a powderedor particulate alkylated cyclodextrin composition, and adding theresulting mixture to a second solution. A sixth method comprisescreating a liquid formulation by any of the above methods and thenisolating a solid material by lyophilization, spray-drying, asepticspray drying, spray-freeze-drying, antisolvent precipitation, a processutilizing a supercritical or near supercritical fluid, or another methodknown to those of ordinary skill in the art to make a powder forreconstitution.

Specific embodiments of the methods of preparing a liquid formulationinclude those wherein: 1) the method further comprises sterile filteringthe formulation using a filtration medium having a pore size of 0.1 μmor larger; 2) the liquid formulation is sterilized by irradiation orautoclaving; 3) the method further comprises isolating a solid from thesolution; 4) the solution is purged with nitrogen or argon or otherinert pharmaceutically acceptable gas such that a substantial portion ofthe oxygen dissolved in, and/or in surface contact with, the solution isremoved.

The disclosure also provides a reconstitutable solid pharmaceuticalcomposition comprising one or more active agents, an alkylatedcyclodextrin composition and optionally at least one otherpharmaceutical excipient. When this composition is reconstituted with anaqueous liquid to form a preserved liquid formulation, it can beadministered by injection, infusion, topically, by inhalation or orallyto a subject.

Some embodiments of the reconstitutable solid pharmaceutical compositionincludes those wherein: 1) the pharmaceutical composition comprises anadmixture of an alkylated cyclodextrin composition and a solidcomprising one or more active agents and optionally at least one solidpharmaceutical excipient, such that a major portion of the active agentis not complexed with an alkylated cyclodextrin prior to reconstitution;and/or 2) the composition comprises a solid mixture of an alkylatedcyclodextrin composition and one or more active agents, wherein a majorportion of the one or more active agents is complexed with the alkylatedcyclodextrin prior to reconstitution.

A composition of the present disclosure can be used in a pharmaceuticaldosage form, pharmaceutical composition or other such combination ofmaterials. These alkylated cyclodextrin compositions are also useful as,but not limited to, analytical reagents, food and cosmetics adjuvantsand/or additives, and as environmental clean-up agents.

CONCLUSION

Various embodiments of the present disclosure have been described above,it should be understood that they have been presented by way of exampleonly, and not limitation. It will be apparent to persons skilled in therelevant art that various changes in form and detail can be made thereinwithout departing from the spirit and scope of the disclosure. Thus, thebreadth and scope of the present disclosure should not be limited by anyof the above-described exemplary embodiments, but should be defined onlyin accordance with the following claims and their equivalents.

All of the various aspects, embodiments, and options described hereincan be combined in any and all variations.

All documents cited herein, including journal articles or abstracts,published or corresponding U.S. or foreign patent applications, issuedor foreign patents, or any other documents, are each entirelyincorporated by reference herein, including all data, tables, figures,and text presented in the cited documents.

What is claimed is:
 1. A process for preparing an alkylated cyclodextrincomposition, the process comprising: (a) mixing a starting cyclodextrinwith an alkylating agent to form a reaction milieu comprising analkylated cyclodextrin; (b) conducting a first one or more separationsto form a first solution comprising the alkylated cyclodextrin, whereinthe one of more separations comprises diafiltration through anultrafiltration membrane; (c) treating the first solution with anactivated carbon to produce a second alkylated cyclodextrin solution;and (d) conducting a second one or more separations to form a thirdalkylated cyclodextrin solution, wherein the one or more separationscomprises nanofiltration through a nanofiltration membrane.
 2. Theprocess of claim 1, wherein solvent is added to dilute the reactionmilieu formed in step (a) prior to conducting the first one or moreseparations.
 3. The process of claim 2, wherein the solvent is water. 4.The process of any one of claims 1 to 3, wherein the concentration ofthe alkylated cyclodextrin in step (b) is less than 10% (w/w) prior tothe first one or more separations.
 5. The process of any one of claims 1to 4, wherein the concentration of the alkylated cyclodextrin in step(b) is less than 8% (w/w) prior to the first one or more separations. 6.The process of any one of claims 1 to 4, wherein the concentration ofthe alkylated cyclodextrin in step (b) is less than 6% (w/w) prior tothe first one or more separations.
 7. The process of any one of claims 1to 4, wherein the concentration of the alkylated cyclodextrin in step(b) is from about 3% (w/w) to about 8% (w/w) prior to the first one ormore separations.
 8. The process of any one of claims 1 to 4, whereinthe concentration of the alkylated cyclodextrin in step (b) is fromabout 4% (w/w) to about 6% (w/w) prior to the first one or moreseparations.
 9. The process of any one of claims 1 to 8, wherein theultrafiltration membrane in step (b) has a molecular weight cut-off(MWCO) of about 1000 Da or lower.
 10. The process of any one of claims 1to 8, wherein the ultrafiltration membrane in step (b) has a MWCO ofabout 1000 Da.
 11. The process of any one of claims 1 to 8, wherein theultrafiltration membrane in step (b) has a MWCO of about 650 Da.
 12. Theprocess of any one of claims 1 to 8, wherein the ultrafiltrationmembrane in step (b) has a MWCO of about 500 Da.
 13. The process of anyone of claims 1 to 8, wherein the ultrafiltration membrane in step (b)has a MWCO of about 500 to about 1000 Da.
 14. The process of any one ofclaims 1 to 13, wherein the activated carbon of step (c) is prepared bya method comprising the step of subjecting the activated carbon to aninitial carbon washing process comprising adding a portion of the firstsolution comprising the alkylated cyclodextrin from step (b) to thecarbon, soaking the carbon in the first solution, and eluting anddiscarding the solution.
 15. The process of claim 14, wherein theactivated carbon of step (c) is further subjected to a washing processcomprising flowing water over the carbon after the initial carbonwashing process and eluting the water.
 16. The process of claim 15,wherein the water is flowed over the carbon for at least 30 minutes. 17.The process of claim 15, wherein the water is flowed over the carbon forat least two hours.
 18. The process of any one of claims 15 to 17,wherein the eluted wash water has a residual conductivity of 10 μS/cm orless
 19. The process of any one of claims 1 to 18, wherein the activatedcarbon is phosphate free.
 20. The process of any one of claims 1 to 19,wherein the activated carbon is steam activated.
 21. The process of anyone of claims 1 to 20, wherein the activated carbon is granular.
 22. Theprocess of any one of claims 1 to 21, wherein the concentration of thealkylated cyclodextrin in the second alkylated cyclodextrin solutionintroduced into step (d) is from about 3% (w/w) to about 8% (w/w). 23.The process of any one of claims 1 to 21, wherein the concentration ofthe alkylated cyclodextrin in the second alkylated cyclodextrin solutionintroduced into step (d) is from about 4% (w/w) to about 7% (w/w). 24.The process of any one of claims 1 to 21, wherein the concentration ofthe alkylated cyclodextrin in the second alkylated cyclodextrin solutionintroduced into step (d) is about 5% (w/w).
 25. The process of any oneof claims 1 to 24, wherein the nanofiltration membrane in step (d) has aMWCO of about 500 Da or lower.
 26. The process of any one of claims 1 to24, wherein the nanofiltration membrane in step (d) has a MWCO of about500 Da.
 27. The process of any one of claims 1 to 24, wherein thenanofiltration membrane in step (d) has a MWCO of about 400 Da.
 28. Theprocess of any one of claims 1 to 24, wherein the nanofiltrationmembrane in step (d) has a MWCO of about 300 Da.
 29. The process of anyone of claims 1 to 24, wherein the nanofiltration membrane in step (d)has a MWCO of about 200 Da.
 30. The process of any one of claims 1 to24, wherein nanofiltration membrane in step (d) has a MWCO of about 150Da.
 31. The process of any one of claims 1 to 24, wherein thenanofiltration membrane in step (d) has a MWCO of about 150-500 Da. 32.The process of any one of claims 1 to 24, wherein nanofiltrationmembrane in step (d) has a MWCO of about 300-500 Da.
 33. The process ofany one of claims 1 to 32, wherein the nanofiltration of step (d) isconducted for a period of 30 minutes to 12 hours.
 34. The process of anyone of claims 1 to 32, wherein the nanofiltration of step (d) isconducted for a period of about 1 hour to about 3 hours.
 35. The processof any one of claims 1 to 32, wherein the nanofiltration of step (d) isconducted for a period of 2 hours.
 36. The process of any one of claims1 to 32, wherein the nanofiltration of step (d) is conducted for aperiod of 3 hours.
 37. The process of any one of claims 1 to 36, whereinthe concentration of the alkylated cyclodextrin in the third alkylatedcyclodextrin solution is from about 10% (w/w) to about 25% (w/w). 38.The process of any one of claims 1 to 36, wherein the concentration ofthe alkylated cyclodextrin in the third alkylated cyclodextrin solutionis from about 15% (w/w) to about 20% (w/w).
 39. The process of any oneof claims 1 to 36, wherein the concentration of the alkylatedcyclodextrin in the third alkylated cyclodextrin solution is about 18%(w/w) to about 20% (w/w).
 40. The process of any one of claims 1 to 40,further comprising concentrating the third alkylated cyclodextrinsolution for a period of about 2 hours to about 24 hours to form afourth alkylated cyclodextrin solution.
 41. The process of anyone ofclaims 1 to 40, further comprising concentrating the third alkylatedcyclodextrin solution for a period of about 6 hours to about 18 hours toform a fourth alkylated cyclodextrin solution.
 42. The process of anyoneof claims 1 to 41, further comprising concentrating the third alkylatedcyclodextrin solution for a period of about 8 hours to about 12 hours toform a fourth alkylated cyclodextrin solution.
 43. The process of anyone of claims 1 to 42, further comprising concentrating the thirdalkylated cyclodextrin solution for a period of about 9 hours to form afourth alkylated cyclodextrin solution.
 44. The process of any one ofclaims 40 to 43, wherein the concentrating the third alkylatedcyclodextrin solution is performed by distillation.
 45. The process ofany one of claims 40 to 44, wherein the concentration of the fourthalkylated cyclodextrin solution is from about 30% (w/w) to about 70%(w/w).
 46. The process of any one of claims 40 to 44, wherein theconcentration of the alkylated cyclodextrin in the fourth alkylatedcyclodextrin solution is from about 40% (w/w) to about 60% (w/w). 47.The process of any one of claims 40 to 44, wherein the concentration ofthe alkylated cyclodextrin in the fourth alkylated cyclodextrin solutionis about 50% (w/w).
 48. The process of any one of claims 1 to 47,further comprising removing the solvent from the fourth alkylatedcyclodextrin solution to form a solid alkylated cyclodextrin.
 49. Theprocess of claim 48, wherein the solvent is removed by distillation,lyophilization, or spray-drying.
 50. The process of any one of claims 48to 49, wherein the solid alkylated cyclodextrin comprises less than 500ppm of a phosphate.
 51. The process of any one of claims 48 to 50,wherein the solid alkylated cyclodextrin comprises less than 125 ppm ofa phosphate.
 52. The process of any one of claims 48 to 51, wherein thesolid alkylated cyclodextrin comprises less than 0.05% (w/w) of achloride.
 53. The process of any one of claims 48 to 52, wherein thesolid alkylated cyclodextrin comprises less than 0.01% (w/w) of achloride.
 54. The process of any one of claims 48 to 53, wherein thesolid alkylated cyclodextrin comprises less than 0.002% (w/w) of achloride.
 55. The process of any one of claims 1 to 54, wherein theprocess comprises preparing a single batch of alkylated cyclodextrinwherein the initial cyclodextrin has a mass greater than 275 kg.
 56. Theprocess of any one of claims 1 to 55, wherein the process comprisespreparing a single batch of alkylated cyclodextrin wherein the initialcyclodextrin has a mass greater than 300 kg.
 57. The process of any oneof claims 1 to 56, wherein the process comprises preparing a singlebatch of alkylated cyclodextrin wherein the initial cyclodextrin has amass greater than 350 kg.
 58. The process of any one of claims 1 to 57,wherein the alkylated cyclodextrin has an average degree of substitutionof 2 to
 9. 59. The process of any one of claims 1 to 58, wherein thealkylated cyclodextrin has an average degree of substitution of 4.5 to7.5.
 60. The process of any one of claims 1 to 59, wherein the alkylatedcyclodextrin has an average degree of substitution of 6 to 7.5.
 61. Theprocess of any one of claims 1 to 60, wherein the alkylated cyclodextrinis a sulfoalkyl ether cyclodextrin of Formula (II):

wherein p is 4, 5, or 6, and R₁ is independently selected at eachoccurrence from —OH or —O—(C₂-C₆ alkylene)-SO₃ ⁻-T, wherein T isindependently selected at each occurrence from pharmaceuticallyacceptable cations, provided that at least one R₁ is —OH and at leastone R₁ is O—(C₂-C₆ alkylene)-SO₃ ⁻-T.
 62. The process of claim 61,wherein R₁ is independently selected at each occurrence from —OH or—O—(C₄ alkylene)-SO₃ ⁻-T, and -T is Na⁺ at each occurrence.
 63. Theprocess of any one of claims 48 to 62, further comprising combining thesolid alkylated cyclodextrin with one or more excipients.
 64. Theprocess of any one of claims 48 to 63, further comprising combining thesolid alkylated cyclodextrin with an active agent.
 65. A productprepared by the process of any one of claims 1 to 64.